Peptide congeners with polymer excipients

ABSTRACT

Provided herein are peptide formulations comprising polymers as stabilizing agents. The peptide formulations can be more stable for prolonged periods of time at temperatures higher than room temperature when formulated with the polymers. The polymers used in the present invention can decrease the degradation of the constituent peptides of the peptide formulations.

CROSS REFERENCE

This application is a continuation of U.S. application Ser. No.15/901,412 filed Feb. 21, 2018, which a continuation of U.S. applicationSer. No. 15/606,442, filed on May 26, 2017, now U.S. Pat. No. 9,937,223,which is a continuation-in-part of U.S. application Ser. No. 15/426,693,filed Feb. 7, 2017, now U.S. Pat. No. 9,744,209, which is acontinuation-in-part of U.S. application Ser. No. 15/289,640, filed Oct.10, 2016, now U.S. Pat. No. 9,687,526, which is a continuation-in-partof U.S. application Ser. No. 14/717,877, filed May 20, 2015, now U.S.Pat. No. 9,744,239, which is a continuation of U.S. application Ser. No.14/610,499, filed Jan. 30, 2015, each of which is incorporated herein byreference in its entirety.

BACKGROUND

Vasopressin is a potent endogenous hormone, responsible for maintainingplasma osmolality and volume in most mammals. Vasopressin can be usedclinically in the treatment of sepsis and cardiac conditions, and in theelevation of patient's suffering from low blood pressure. Currentformulations of vasopressin suffer from poor long-term stability.

INCORPORATION BY REFERENCE

Each patent, publication, and non-patent literature cited in theapplication is hereby incorporated by reference in its entirety as ifeach was incorporated by reference individually.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Feb. 16, 2018, isnamed 47956702314_SL.txt and is 5266 bytes in size.

SUMMARY OF THE INVENTION

In some embodiments, the invention provides a pharmaceutical compositioncomprising, in a unit dosage form: a) from about 0.01 mg/mL to about0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable saltthereof; and b) a polymeric pharmaceutically-acceptable excipient in anamount that is from about 1% to about 10% by mass of the unit dosageform or the pharmaceutically-acceptable salt thereof, wherein the unitdosage form exhibits from about 5% to about 10% less degradation of thevasopressin or the pharmaceutically-acceptable salt thereof afterstorage for about 1 week at about 60° C. than does a corresponding unitdosage form, wherein the corresponding unit dosage form consistsessentially of: A) vasopressin, or a pharmaceutically-acceptable saltthereof; and B) a buffer having acidic pH.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a chromatogram of a diluent used in vasopressin assay.

FIG. 2 is a chromatogram of a sensitivity solution used in a vasopressinassay.

FIG. 3 is a chromatogram of an impurity marker solution used in avasopressin assay.

FIG. 4 is a zoomed-in depiction of the chromatogram in FIG. 3.

FIG. 5 is a chromatogram of a vasopressin standard solution.

FIG. 6 is a chromatogram of a sample vasopressin preparation.

FIG. 7 is a UV spectrum of a vasopressin sample.

FIG. 8 is a UV spectrum of a vasopressin standard.

FIG. 9 plots vasopressin stability across a range of pH as determinedexperimentally.

FIG. 10 illustrates the effects of various stabilizers on vasopressinstability.

FIG. 11 plots vasopressin stability across a range of pH at 25° C.

FIG. 12 plots vasopressin impurities across a range of pH at 25° C.

FIG. 13 plots vasopressin stability across a range of pH at 40° C.

FIG. 14 plots vasopressin impurities across a range of pH at 40° C.

FIG. 15 illustrates vasopressin impurities across a range of pH at 25°C.

FIG. 16 illustrates vasopressin impurities across a range of pH at 40°C.

FIG. 17 illustrates the effect of pH on vasopressin at 25° C.

FIG. 18 illustrates the effect of pH on vasopressin at 40° C.

FIG. 19 depicts the % LC of vasopressin formulations stored for 15months at 25° C.

FIG. 20 below shows a diagram of a cap to be used on a vial describedherein.

FIG. 21 depicts a stopper to be used in a vial described herein.

FIG. 22 shows a vial for use in storing a 10 mL vasopressin formulationdescribed herein.

FIG. 23 shows the vasopressin assay results (represented as % labelclaim) of studies performed at 25° C. with upright storage.

FIG. 24 shows the vasopressin assay results (represented as % labelclaim) of the studies performed at 25° C. with inverted storage.

FIG. 25 shows the amount of Gly9-AVP when a 10 mL vasopressinformulation was stored at 25° C. in an upright position.

FIG. 26 shows the amount of Gly9-AVP when a 10 mL vasopressinformulation was stored at 25° C. in an inverted position.

FIG. 27 shows the amount of Glu4-AVP when a 10 mL vasopressinformulation was stored at 25° C. in an upright position.

FIG. 28 shows the amount of Glu4-AVP when a 10 mL vasopressinformulation was stored at 25° C. in an inverted position.

FIG. 29 shows the total impurities when a 10 mL vasopressin formulationwas stored at 25° C. in an upright position.

FIG. 30 shows the total impurities when a 10 mL vasopressin formulationwas stored at 25° C. in an inverted position.

DETAILED DESCRIPTION

Vasopressin and peptides of the invention.

Vasopressin, a peptide hormone, acts to regulate water retention in thebody and is a neurotransmitter that controls circadian rhythm,thermoregulation, and adrenocorticotrophic hormone (ACTH) release.Vasopressin is synthesized as a pro-hormone in neurosecretory cells ofthe hypothalamus, and is subsequently transported to the pituitary glandfor storage. Vasopressin is released upon detection of hyperosmolalityin the plasma, which can be due to dehydration of the body. Uponrelease, vasopressin increases the permeability of collecting ducts inthe kidney to reduce renal excretion of water. The decrease in renalexcretion of water leads to an increase in water retention of the bodyand an increase in blood volume. At higher concentrations, vasopressinraises blood pressure by inducing vasoconstriction.

Vasopressin acts through various receptors in the body including, forexample, the V1, V2, V3, and oxytocin-type (OTR) receptors. The V1receptors occur on vascular smooth muscle cells, and the major effect ofvasopressin action on the V1 receptor is the induction ofvasoconstriction via an increase of intracellular calcium. V2 receptorsoccur on the collecting ducts and the distal tubule of the kidney. V2receptors play a role in detection of plasma volume and osmolality. V3receptors occur in the pituitary gland and can cause ACTH release uponvasopressin binding. OTRs can be found on the myometrium and vascularsmooth muscle. Engagement of OTRs via vasopressin leads to an increaseof intracellular calcium and vasoconstriction.

Vasopressin is a nonapeptide, illustrated below (SEQ ID NO. 1):

At neutral to acidic pH, the two basic groups of vasopressin, theN-terminal cysteine, and the arginine at position eight, are protonated,and can each carry an acetate counterion. The amide groups of theN-terminal glycine, the glutamine at position four, and the asparagineat position five, are susceptible to modification when stored asclinical formulations, such as unit dosage forms. The glycine,glutamine, and asparagine residues can undergo deamidation to yield theparent carboxylic acid and several degradation products as detailed inEXAMPLE 1 and TABLE 1 below.

Deamidation is a peptide modification during which an amide group isremoved from an amino acid, and can be associated with proteindegradation, apoptosis, and other regulatory functions within the cell.Deamidation of asparagine and glutamine residues can occur in vitro andin vivo, and can lead to perturbation of the structure and function ofthe affected proteins. The susceptibility to deamidation can depend onprimary sequence of the protein, three-dimensional structure of theprotein, and solution properties including, for example, pH,temperature, ionic strength, and buffer ions. Deamidation can becatalyzed by acidic conditions. Under physiological conditions,deamidation of asparagine occurs via the formation of a five-memberedsuccinimide ring intermediate by a nucleophilic attack of the nitrogenatom in the following peptide bond on the carbonyl group of theasparagine side chain. Acetylation is a peptide modification whereby anacetyl group is introduced into an amino acid, such as on the N-terminusof the peptide.

Vasopressin can also form dimers in solution and in vivo. Thevasopressin dimers can occur through the formation of disulfide bridgesthat bind a pair of vasopressin monomers together. The dimers can formbetween two parallel or anti-parallel chains of vasopressin.

Vasopressin and associated degradation products or peptides are listedin TABLE 1 below. All amino acids are L-stereoisomers unless otherwisedenoted.

TABLE 1 SEQ Name Sequence ID NO. Vasopressin (AVP; arginineCYFQNCPRG-NH₂ 1 vasopressin) Gly9-vasopressin (Gly9-AVP) CYFQNCPRG 2Asp5-vasopressin (Asp5-AVP) CYFQDCPRG-NH₂ 3 Glu4-vasopressin (Glu4-AVP)CYFENCPRG-NH₂ 4 Glu4Gly9-vasopressin (Glu4Gly9- CYFENCPRG 5 AVP)AcetylAsp5-vasopressin Ac-CYFQDCPRG-NH₂ 6 (AcetylAsp5-AVP)Acetyl-vasopressin (Acetyl-AVP) Ac-CYFQNCPRG-NH₂ 7 His2-vasopressin(His2-AVP) CHFQNCPRG-NH₂ 8 Leu7-vasopressin (Leu7-AVP) CYFQNCLRG-NH₂ 9D-Asn-vasopressin (DAsn-AVP) CYFQ(D-Asn)CPRG-NH₂ 10 D-Cys1-vasopressin(D-Cys)YFQNCPRG-NH₂ 11 D-Tyr-vasopressin C(D-Tyr)FQNCPRG-NH₂ 12D-Phe-vasopressin CY(D-Phe)QNCPRG-NH₂ 13 D-Gln-vasopressinCYF(D-Gln)NCPRG-NH₂ 14 D-Cys6-vasopressin CYFQN(D-cys)PRG-NH₂ 15D-Pro-vasopressin CYFQNC(D-pro)RG-NH₂ 16 D-Arg-vasopressinCYFQNCP(D-Arg)G-NH₂ 17

Therapeutic Uses.

A formulation of vasopressin can be used to regulate plasma osmolalityand volume and conditions related to the same in a subject. Vasopressincan be used to modulate blood pressure in a subject, and can beindicated in a subject who is hypotensive despite treatment with fluidand catecholamines.

Vasopressin can be used in the treatment of, for example, vasodilatoryshock, post-cardiotomy shock, sepsis, septic shock, cranial diabetesinsipidus, polyuria, nocturia, polydypsia, bleeding disorders, VonWillebrand disease, haemophilia, platelet disorders, cardiac arrest,liver disease, liver failure, hypovolemia, hemorrhage, oesophagealvariceal haemorrhage, hypertension, pulmonary hypertension, renaldisease, polycystic kidney disease, blood loss, injury, hypotension,meniere disease, uterine myomas, brain injury, mood disorder.Formulations of vasopressin can be administered to a subject undergoing,for example, surgery or hysterectomy.

Plasma osmolality is a measure of the plasma's electrolyte-water balanceand relates to blood volume and hydration of a subject. Normal plasmaosmolality in a healthy human subject range from about 275milliosmoles/kg to about 295 milliosmoles/kg. High plasma osmolalitylevels can be due to, for example, diabetes insipidus, hyperglycemia,uremia, hypernatremia, stroke, and dehydration. Low plasma osmolalitycan be due to, for example, vasopressin oversecretion, improperfunctioning of the adrenal gland, lung cancer, hyponatremia,hypothyroidism, and over-consumption of water or other fluids. Septicshock can develop due to an extensive immune response followinginfection and can result in low blood pressure. Causes of sepsis caninclude, for example, gastrointestinal infections, pneumonia,bronchitis, lower respiratory tract infections, kidney infection,urinary tract infections, reproductive system infections, fungalinfections, and viral infections. Risk factors for sepsis include, forexample, age, prior illness, major surgery, long-term hospitalization,diabetes, intravenous drug use, cancer, use of steroidal medications,and long-term use of antibiotics. The symptoms of sepsis can include,for example, cool arms and legs, pale arms and legs, extreme bodytemperatures, chills, light-headedness, decreased urination, rapidbreathing, edema, confusion, elevated heart rate, high blood sugar,metabolic acidosis, respiratory alkalosis, and low blood pressure.

Vasopressin can also be administered to regulate blood pressure in asubject. Blood pressure is the measure of force of blood pushing againstblood vessel walls. Blood pressure is regulated by the nervous andendocrine systems and can be used as an indicator of a subject's health.Chronic high blood pressure is referred to as hypertension, and chroniclow blood pressure is referred to as hypotension. Both hypertension andhypotension can be harmful if left untreated.

Blood pressure can vary from minute to minute and can follow thecircadian rhythm with a predictable pattern over a 24-hour period. Bloodpressure is recorded as a ratio of two numbers: systolic pressure (mmHg), the numerator, is the pressure in the arteries when the heartcontracts, and diastolic pressure (mm Hg), the denominator, is thepressure in the arteries between contractions of the heart. Bloodpressure can be affected by, for example, age, weight, height, sex,exercise, emotional state, sleep, digestion, time of day, smoking,alcohol consumption, salt consumption, stress, genetics, use of oralcontraceptives, and kidney disease.

Blood pressure for a healthy human adult between the ages of 18-65 canrange from about 90/60 to about 120/80. Hypertension can be a bloodpressure reading above about 120/80 and can be classified ashypertensive crisis when there is a spike in blood pressure and bloodpressure readings reach about 180/110 or higher. Hypertensive crisis canbe precipitated by, for example, stroke, myocardial infarction, heartfailure, kidney failure, aortic rupture, drug-drug interactions, andeclampsia. Symptoms of hypertensive crisis can include, for example,shortness of breath, angina, back pain, numbness, weakness, dizziness,confusion, change in vision, nausea, and difficulty speaking.

Vasodilatory shock can be characterized by low arterial blood pressuredue to decreased systemic vascular resistance. Vasodilatory shock canlead to dangerously low blood pressure levels and can be corrected viaadministration of catecholamines or vasopressin formulations.Vasodilatory shock can be caused by, for example, sepsis, nitrogenintoxication, carbon monoxide intoxication, hemorrhagic shock,hypovolemia, heart failure, cyanide poisoning, metformin intoxication,and mitochondrial disease.

Post-cardiotomy shock can occur as a complication of cardiac surgery andcan be characterized by, for example, inability to wean fromcardiopulmonary bypass, poor hemodynamics in the operating room,development of poor hemodynamics post-surgery, and hypotension.

Pharmaceutical Formulations.

Methods for the preparation of compositions comprising the compoundsdescribed herein can include formulating the compounds with one or moreinert, pharmaceutically-acceptable excipients. Liquid compositionsinclude, for example, solutions in which a compound is dissolved,emulsions comprising a compound, or a solution containing liposomes,micelles, or nanoparticles comprising a compound as disclosed herein.These compositions can also contain minor amounts of nontoxic, auxiliarysubstances, such as wetting or emulsifying agents, pH buffering agents,and other pharmaceutically-acceptable additives.

Non-limiting examples of dosage forms suitable for use in the disclosureinclude liquid, elixir, nanosuspension, aqueous or oily suspensions,drops, syrups, and any combination thereof. Non-limiting examples ofpharmaceutically-acceptable excipients suitable for use in thedisclosure include granulating agents, binding agents, lubricatingagents, disintegrating agents, anti-adherents, anti-static agents,surfactants, anti-oxidants, coloring agents, flavoring agents,plasticizers, preservatives, suspending agents, emulsifying agents,plant cellulosic material and spheronization agents, and any combinationthereof.

Vasopressin can be formulated as an aqueous formulation or a lyophilizedpowder, which can be diluted or reconstituted just prior to use. Upondilution or reconstitution, the vasopressin solution can be refrigeratedfor long-term stability for about one day. Room temperature incubationor prolonged refrigeration can lead to the generation of degradationproducts of vasopressin.

In some embodiments, a pharmaceutical composition of the invention canbe formulated for long-term storage of vasopressin at room temperaturein the presence of a suitable pharmaceutically-acceptable excipient. Thepharmaceutically-acceptable excipient can increase the half-life ofvasopressin when stored at any temperature, such as room temperature.The presence of the pharmaceutical excipient can decrease the rate ofdecomposition of vasopressin at any temperature, such as roomtemperature.

In some embodiments, a pharmaceutical composition has a shelf life of atleast about 12 months, at least about 13 months, at least about 14months, at least about 15 months, at least about 16 months, at leastabout 17 months, at least about 18 months, at least about 19 months, atleast about 20 months, at least about 21 months, at least about 22months, at least about 23 months, at least about 24 months, at leastabout 25 months, at least about 26 months, at least about 27 months, atleast about 28 months, at least about 29 months, or at least about 30months. The shelf life can be at any temperature, including, forexample, room temperature and refrigeration (i.e., 2-8° C.). As usedherein, “shelf life” means the period beginning from manufacture of aformulation beyond which the formulation cannot be expected beyondreasonable doubt to yield the therapeutic outcome approved by agovernment regulatory agency

In some embodiments, a vasopressin formulation of the inventioncomprises a pharmaceutically-acceptable excipient, and the vasopressinhas a half-life that is at least about 1%, at least about 5%, at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 30%, at least about 35%, at least about 40%, at leastabout 45%, at least about 50%, at least about 55%, at least about 60%,at least about 65%, at least about 70%, at least about 75%, at leastabout 80%, at least about 85%, at least about 90%, at least about 95%,at least about 100%, at least about 150%, at least about 200%, at leastabout 250%, at least about 300%, at least about 350%, at least about400%, at least about 450%, at least about 500%, at least about 600%, atleast about 700%, at least about 800%, at least about 900%, or at leastabout 1000% greater than the half-life of vasopressin in a correspondingformulation that lacks the pharmaceutically-acceptable excipient.

In some embodiments, a vasopressin formulation of the invention has ahalf-life at about 5° C. to about 8° C. that is no more than about 1%,no more than about 5%, no more than about 10%, no more than about 15%,no more than about 20%, no more than about 25%, no more than about 30%,no more than about 35%, no more than about 40%, no more than about 45%,no more than about 50%, no more than about 55%, no more than about 60%,no more than about 65%, no more than about 70%, no more than about 75%,no more than about 80%, no more than about 85%, no more than about 90%,no more than about 95%, no more than about 100%, no more than about150%, no more than about 200%, no more than about 250%, no more thanabout 300%, no more than about 350%, no more than about 400%, no morethan about 450%, no more than about 500%, no more than about 600%, nomore than about 700%, no more than about 800%, no more than about 900%,or no more than about 1000% greater than the half-life of theformulation at another temperature, such as room temperature.

The half-life of the compounds of the invention in a formulationdescribed herein at a specified temperature can be, for example, about 1hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours,about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours,about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24hours, about 30 hours, about 36 hours, about 42 hours, about 48 hours,about 60 hours, about 3 days, about 4 days, about 5 days, about 6 days,or about one week.

A formulation described herein can be stable for or be stored for, forexample, about 1 hour, about 2 hours, about 3 hours, about 4 hours,about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours,about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours,about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks,about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4months, about 5 months, about 6 months, about 7 months, about 8 months,about 9 months, about 10 months, about 11 months, about 1 year, about 13months, about 14 months, about 15 months, about 16 months, about 17months, about 18 months, about 19 months, about 20 months, about 21months, about 22 months, about 23 months, about 2 years, about 25months, about 26 months, about 27 months, about 28 months, about 29months, about 30 months, about 31 months, about 32 months, about 33months, about 34 months, about 35 months, or about 3 years prior toadministration to a subject.

A unit dosage form described herein can be stable for or be stored for,for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours,about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours,about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours,about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks,about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4months, about 5 months, about 6 months, about 7 months, about 8 months,about 9 months, about 10 months, about 11 months, about 1 year, about 13months, about 14 months, about 15 months, about 16 months, about 17months, about 18 months, about 19 months, about 20 months, about 21months, about 22 months, about 23 months, about 2 years, about 25months, about 26 months, about 27 months, about 28 months, about 29months, about 30 months, about 31 months, about 32 months, about 33months, about 34 months, about 35 months, or about 3 years prior toadministration to a subject.

A diluted unit dosage form described herein can be stable for or bestored for, for example, about 1 hour, about 2 hours, about 3 hours,about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours,about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours,about 22 hours, about 23 hours, about 24 hours, about 30 hours, about 36hours, about 42 hours, about 48 hours, about 60 hours, about 3 days,about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks,about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks,about 3 months, about 4 months, about 5 months, about 6 months, about 7months, about 8 months, about 9 months, about 10 months, about 11months, about 1 year, about 13 months, about 14 months, about 15 months,about 16 months, about 17 months, about 18 months, about 19 months,about 20 months, about 21 months, about 22 months, about 23 months,about 2 years, about 25 months, about 26 months, about 27 months, about28 months, about 29 months, about 30 months, about 31 months, about 32months, about 33 months, about 34 months, about 35 months, or about 3years prior to administration to subject.

The stability of a formulation described herein can be measured after,for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours,about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours,about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours,about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks,about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4months, about 5 months, about 6 months, about 7 months, about 8 months,about 9 months, about 10 months, about 11 months, about 1 year, about 13months, about 14 months, about 15 months, about 16 months, about 17months, about 18 months, about 19 months, about 20 months, about 21months, about 22 months, about 23 months, about 2 years, about 25months, about 26 months, about 27 months, about 28 months, about 29months, about 30 months, about 31 months, about 32 months, about 33months, about 34 months, about 35 months, or about 3 years.

A formulation or unit dosage form described herein can exhibit, forexample, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%,about 0.6%, about 0.7%, about 0.8%, about 0.9% about 1%, about 1.1%,about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%,about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%,about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%,about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%,about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%,about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%,about 4.8%, about 4.9%, about 5%, about 5.5%, about 6%, about 6.5%,about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, orabout 10% degradation over a specified period of time. The degradationof a formulation or a unit dosage form disclosed herein can be assessedafter about 24 hours, about 36 hours, about 72 hours, about 96 hours,about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5weeks, about 6 weeks, about 2 months, about 3 months, about 4 months,about 5 months, about 6 months, about 8 months, about 10 months, about 1year, about 13 months, about 14 months, about 15 months, about 16months, about 17 months, about 18 months, about 19 months, about 20months, about 21 months, about 22 months, about 23 months, about 2years, about 25 months, about 26 months, about 27 months, about 28months, about 29 months, about 30 months, about 31 months, about 32months, about 33 months, about 34 months, about 35 months, or about 3years of storage. The degradation of a formulation or a unit dosage formdisclosed herein can be assessed at a temperature of, for example, about0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C.,about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about11° C., about 12° C., about 13° C., about 14° C., about 15° C., about16° C., about 17° C., about 18° C., about 19° C., about 20° C., about21° C., about 22° C., about 23° C., about 24° C., about 25° C., about26° C., about 27° C., about 28° C., about 29° C., about 30° C., about31° C., about 32° C., about 33° C., about 34° C., about 35° C., about36° C., about 37° C., about 38° C., about 39° C., about 40° C., about41° C., about 42° C., about 43° C., about 44° C., about 45° C., about46° C., about 47° C., about 48° C., about 49° C., about 50° C., or about0° C. to about 5° C., about 1° C. to about 6° C., about 2° C. to about7° C., about 2° C. to about 8° C., about 3° C. to about 8° C., about 4°C. to about 9° C., about 5° C. to about 10° C., about 6° C. to about 11°C., about 7° C. to about 12° C., about 8° C. to about 13° C., about 9°C. to about 14° C., about 10° C. to about 15° C., about 11° C. to about16° C., about 12° C. to about 17° C., about 13° C. to about 18° C.,about 14° C. to about 19° C., about 15° C. to about 20° C., about 16° C.to about 21° C., about 17° C. to about 22° C., about 18° C. to about 23°C., about 19° C. to about 24° C., about 20° C. to about 25° C., about21° C. to about 26° C., about 22° C. to about 27° C., about 23° C. toabout 28° C., about 24° C. to about 29° C., about 25° C. to about 30°C., about 26° C. to about 31° C., about 27° C. to about 32° C., about28° C. to about 33° C., about 29° C. to about 34° C., about 30° C. toabout 35° C., about 31° C. to about 36° C., about 32° C. to about 37°C., about 33° C. to about 38° C., about 34° C. to about 39° C., about35° C. to about 40° C., about 36° C. to about 41° C., about 37° C. toabout 42° C., about 38° C. to about 43° C., about 39° C. to about 44°C., about 40° C. to about 45° C., about 41° C. to about 46° C., about42° C. to about 47° C., about 43° C. to about 48° C., about 44° C. toabout 49° C., about 45° C. to about 50° C.

In some embodiments, a vasopressin formulation of the inventioncomprises an excipient and the vasopressin has a level of decompositionat a specified temperature that is about 0.1%, about 0.2%, about 0.3%,about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%,about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%,about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%,about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%,about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%,about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%,about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%,about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 10%,about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90%, about 95%, about 100%, about 150%,about 200%, about 250%, about 300%, about 350%, about 400%, about 450%,about 500%, about 600%, about 700%, about 800%, about 900%, or about1000% less than the level of decomposition of a formulation of theinvention in the absence of the excipient.

Pharmaceutical compositions of the invention can be used, stored,tested, analyzed or assayed at any suitable temperature. Non-limitingexamples of temperatures include about 0° C., about 1° C., about 2° C.,about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13°C., about 14° C., about 15° C., about 16° C., about 17° C., about 18°C., about 19° C., about 20° C., about 21° C., about 22° C., about 23°C., about 24° C., about 25° C., about 26° C., about 27° C., about 28°C., about 29° C., about 30° C., about 31° C., about 32° C., about 33°C., about 34° C., about 35° C., about 36° C., about 37° C., about 38°C., about 39° C., about 40° C., about 41° C., about 42° C., about 43°C., about 44° C., about 45° C., about 46° C., about 47° C., about 48°C., about 49° C., about 50° C., about 51° C., about 52° C., about 53°C., about 54° C., about 55° C., about 56° C., about 57° C., about 58°C., about 59° C., about 60° C., about 61° C., about 62° C., about 63°C., about 64° C., about 65° C., about 66° C., about 67° C., about 68°C., about 69° C., about 70° C., about 71° C., about 72° C., about 73°C., about 74° C., or about 75° C.

Pharmaceutical compositions of the invention can be used, stored,tested, analyzed or assayed at any suitable temperature. Non-limitingexamples of temperatures include from about 0° C. to about 5° C., about1° C. to about 6° C., about 2° C. to about 7° C., about 2° C. to about8° C., about 3° C. to about 8° C., about 4° C. to about 9° C., about 5°C. to about 10° C., about 6° C. to about 11° C., about 7° C. to about12° C., about 8° C. to about 13° C., about 9° C. to about 14° C., about10° C. to about 15° C., about 11° C. to about 16° C., about 12° C. toabout 17° C., about 13° C. to about 18° C., about 14° C. to about 19°C., about 15° C. to about 20° C., about 16° C. to about 21° C., about17° C. to about 22° C., about 18° C. to about 23° C., about 19° C. toabout 24° C., about 20° C. to about 25° C., about 21° C. to about 26°C., about 22° C. to about 27° C., about 23° C. to about 28° C., about24° C. to about 29° C., about 25° C. to about 30° C., about 26° C. toabout 31° C., about 27° C. to about 32° C., about 28° C. to about 33°C., about 29° C. to about 34° C., about 30° C. to about 35° C., about31° C. to about 36° C., about 32° C. to about 37° C., about 33° C. toabout 38° C., about 34° C. to about 39° C., about 35° C. to about 40°C., about 36° C. to about 41° C., about 37° C. to about 42° C., about38° C. to about 43° C., about 39° C. to about 44° C., about 40° C. toabout 45° C., about 41° C. to about 46° C., about 42° C. to about 47°C., about 43° C. to about 48° C., about 44° C. to about 49° C., about45° C. to about 50° C., about 46° C. to about 51° C., about 47° C. toabout 52° C., about 48° C. to about 53° C., about 49° C. to about 54°C., about 50° C. to about 55° C., about 51° C. to about 56° C., about52° C. to about 57° C., about 53° C. to about 58° C., about 54° C. toabout 59° C., about 55° C. to about 60° C., about 56° C. to about 61°C., about 57° C. to about 62° C., about 58° C. to about 63° C., about59° C. to about 64° C., about 60° C. to about 65° C., about 61° C. toabout 66° C., about 62° C. to about 67° C., about 63° C. to about 68°C., about 64° C. to about 69° C., about 65° C. to about 70° C., about66° C. to about 71° C., about 67° C. to about 72° C., about 68° C. toabout 73° C., about 69° C. to about 74° C., about 70° C. to about 74°C., about 71° C. to about 76° C., about 72° C. to about 77° C., about73° C. to about 78° C., about 74° C. to about 79° C., or about 75° C. toabout 80° C.

Pharmaceutical compositions of the invention can be used, stored,tested, analyzed or assayed at room temperature. The room temperaturecan be, for example, about 20.0° C., about 20.1° C., about 20.2° C.,about 20.3° C., about 20.4° C., about 20.5° C., about 20.6° C., about20.7° C., about 20.8° C., about 20.9° C., about 21.0° C., about 21.1°C., about 21.2° C., about 21.3° C., about 21.4° C., about 21.5° C.,about 21.6° C., about 21.7° C., about 21.8° C., about 21.9° C., about22.0° C., about 22.1° C., about 22.2° C., about 22.3° C., about 22.4°C., about 22.5° C., about 22.6° C., about 22.7° C., about 22.8° C.,about 22.9° C., about 23.0° C., about 23.1° C., about 23.2° C., about23.3° C., about 23.4° C., about 23.5° C., about 23.6° C., about 23.7°C., about 23.8° C., about 23.9° C., about 24.0° C., about 24.1° C.,about 24.2° C., about 24.3° C., about 24.4° C., about 24.5° C., about24.6° C., about 24.7° C., about 24.8° C., about 24.9° C., or about 25.0°C.

A pharmaceutical composition of the disclosed can be supplied, stored,or delivered in a vial or tube that is, for example, about 0.5 mL, about1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about7 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL,about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about18 mL, about 19 mL, or about 20 mL in volume.

A pharmaceutical composition of the disclosure can be a combination ofany pharmaceutical compounds described herein with other chemicalcomponents, such as carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. Pharmaceutical compositions can be administered intherapeutically-effective amounts, for example, intravenous,subcutaneous, intramuscular, transdermal, or parenteral administration.

Pharmaceutical preparations can be formulated for intravenousadministration. The pharmaceutical compositions can be in a formsuitable for parenteral injection as a sterile suspension, solution, oremulsion in oily or aqueous vehicles, and can contain formulation agentssuch as suspending, stabilizing, and/or dispersing agents.Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Suspensions of the active compounds can be prepared as oily injectionsuspensions. Suitable lipophilic solvents or vehicles include fatty oilssuch as sesame oil, or synthetic fatty acid esters, such as ethyl oleateor triglycerides, or liposomes. Aqueous injection suspensions cancontain substances which increase the viscosity of the suspension, suchas sodium carboxymethyl cellulose, sorbitol, or dextran. The suspensioncan also contain suitable stabilizers or agents which increase thesolubility of the compounds to allow for the preparation of highlyconcentrated solutions. Alternatively, the active ingredient can be inpowder form for constitution with a suitable vehicle, for example,sterile pyrogen-free water, before use.

Comparison Formulations.

A pharmaceutical composition described herein can be analyzed bycomparison to a reference formulation. A reference formulation can begenerated from any combination of compounds, peptides, excipients,diluents, carriers, and solvents disclosed herein. Any compound,peptide, excipient, diluent, carrier, or solvent used to generate thereference formulation can be present in any percentage, ratio, oramount, for example, those disclosed herein. The reference formulationcan comprise, consist essentially of, or consist of any combination ofany of the foregoing.

A non-limiting example of a comparison formulation comprises, consistsessentially of, or consists of: an amount, such as about 20 Units orabout 0.04 mg, of vasopressin or a pharmaceutically-acceptable saltthereof, an amount, such as about 5 mg, of chlorobutanol (for example,hydrous), an amount, such as about 0.22 mg, of acetic acid or apharmaceutically-acceptable salt thereof or a quantity sufficient tobring pH to about 3.4 to about 3.6, and water as needed. Anothernon-limiting example of a comparison formulation comprises, consistsessentially of, or consists of: vasopressin or apharmaceutically-acceptable salt thereof, chlorobutanol, acetic acid,and a solvent such as water. Another non-limiting example of acomparison formulation comprises, consists essentially of, or consistsof: vasopressin or a pharmaceutically-acceptable salt thereof,chlorobutanol, and a solvent such as water. Another non-limiting exampleof a comparison formulation comprises, consists essentially of, orconsists of: vasopressin or a pharmaceutically-acceptable salt thereof,acetic acid, and a solvent such as water. Another non-limiting exampleof a comparison formulation comprises, consists essentially of, orconsists of: vasopressin or a pharmaceutically-acceptable salt thereofand a solvent such as water. Another non-limiting example of acomparison formulation comprises, consists essentially of, or consistsof: vasopressin or a pharmaceutically-acceptable salt thereof and abuffer having acidic pH, such as pH 3.5 or any buffer or pH describedherein.

Methods.

Any formulation described herein can be diluted prior to administrationto a subject.

Diluents that can be used in a method of the invention include, forexample, compound sodium lactate solution, 6% dextran, 10% dextran, 5%dextrose, 20% fructose, Ringer's solution, 5% saline, 1.39% sodiumbicarbonate, 1.72% sodium lactate, or water. Upon dilution, any dilutedformulation disclosed herein can be stored for, for example, about 24hours, about 36 hours, about 72 hours, about 96 hours, about 1 week,about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6weeks, about 2 months, about 3 months, about 4 months, about 5 months,about 6 months, about 8 months, about 10 months, about 1 year, about 13months, about 14 months, about 15 months, about 16 months, about 17months, about 18 months, about 19 months, about 20 months, about 21months, about 22 months, about 23 months, about 2 years, about 25months, about 26 months, about 27 months, about 28 months, about 29months, about 30 months, about 31 months, about 32 months, about 33months, about 34 months, about 35 months, or about 3 years of storage.Upon dilution, any diluted formulation disclosed herein can be storedat, for example, about 0° C., about 1° C., about 2° C., about 3° C.,about 4° C., about 5° C., about 6° C., about 7° C., about 8° C., about9° C., about 10° C., about 11° C., about 12° C., about 13° C., about 14°C., about 15° C., about 16° C., about 17° C., about 18° C., about 19°C., about 20° C., about 21° C., about 22° C., about 23° C., about 24°C., about 25° C., about 26° C., about 27° C., about 28° C., about 29°C., about 30° C., about 31° C., about 32° C., about 33° C., about 34°C., about 35° C., about 36° C., about 37° C., about 38° C., about 39°C., about 40° C., about 41° C., about 42° C., about 43° C., about 44°C., about 45° C., about 46° C., about 47° C., about 48° C., about 49°C., about 50° C., or about 0° C. to about 5° C., about 1° C. to about 6°C., about 2° C. to about 7° C., about 2° C. to about 8° C., about 3° C.to about 8° C., about 4° C. to about 9° C., about 5° C. to about 10° C.,about 6° C. to about 11° C., about 7° C. to about 12° C., about 8° C. toabout 13° C., about 9° C. to about 14° C., about 10° C. to about 15° C.,about 11° C. to about 16° C., about 12° C. to about 17° C., about 13° C.to about 18° C., about 14° C. to about 19° C., about 15° C. to about 20°C., about 16° C. to about 21° C., about 17° C. to about 22° C., about18° C. to about 23° C., about 19° C. to about 24° C., about 20° C. toabout 25° C., about 21° C. to about 26° C., about 22° C. to about 27°C., about 23° C. to about 28° C., about 24° C. to about 29° C., about25° C. to about 30° C., about 26° C. to about 31° C., about 27° C. toabout 32° C., about 28° C. to about 33° C., about 29° C. to about 34°C., about 30° C. to about 35° C., about 31° C. to about 36° C., about32° C. to about 37° C., about 33° C. to about 38° C., about 34° C. toabout 39° C., about 35° C. to about 40° C., about 36° C. to about 41°C., about 37° C. to about 42° C., about 38° C. to about 43° C., about39° C. to about 44° C., about 40° C. to about 45° C., about 41° C. toabout 46° C., about 42° C. to about 47° C., about 43° C. to about 48°C., about 44° C. to about 49° C., about 45° C. to about 50° C.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 24 hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 48 hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 96 hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about one week.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about two weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about0.21 μg/mL to about 2.1 μg/mL) of vasopressin or apharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) aceticacid; and iv) water; b) storing the unit dosage form at 2-8° C., forexample, 5° C., for at least 4 weeks; c) diluting the unit dosage formin a diluent to provide a concentration from about 0.1 units/mL to about1 unit/mL of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about three weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about0.21 μg/mL to about 2.1 μg/mL) of vasopressin or apharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) aceticacid; and iv) water; b) storing the unit dosage form at 2-8° C., forexample, 5° C., for at least 4 weeks; c) diluting the unit dosage formin a diluent to provide a concentration from about 0.1 units/mL to about1 unit/mL of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about four weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL (about0.21 μg/mL to about 2.1 μg/mL) of vasopressin or apharmaceutically-acceptable salt thereof; ii) chlorobutanol; iii) aceticacid; and iv) water; b) storing the unit dosage form at 2-8° C., forexample, 5° C., for at least 4 weeks; c) diluting the unit dosage formin a diluent to provide a concentration from about 0.1 units/mL to about1 unit/mL of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about six weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about three months.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about six months.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about one year.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about two years.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about three years.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 24 hours; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 4 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 48 hours; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 4 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 96 hours; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 4 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 1 week; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 4 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 4 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 4 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about one week.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 6 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 4 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 3 months; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 4 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 6 months; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 4 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least one year; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 4 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least two years; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 4 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least three years; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 4 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 24 hours; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 24 hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 48 hours; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 48 hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 96 hours; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 96 hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least one week; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about one week.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 2 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 3 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 4 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 3 months; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 3 months.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 6 months; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 6 months.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 1 year; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 1 year.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 2 years; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 2 years.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 3 years; c)diluting the unit dosage form in a diluent to provide a concentrationfrom about 0.1 units/mL to about 1 unit/mL (about 0.21 μg/mL to about2.1 μg/mL) of vasopressin or the pharmaceutically-acceptable saltthereof; and d) administering the diluted unit dosage form to the humanby intravenous administration; wherein: the administration provides tothe human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; and the human is hypotensive, wherein the unit dosage formexhibits less than about 5% degradation after storage at 2-8° C., forexample, 5° C., for about 3 years.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 24 hours; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 4weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 48 hours; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 4weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 96 hours; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 4weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 1 week; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 4weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 4weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 4weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about oneweek.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 3 months; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 4weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 6 months; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 4weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 1 year; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 4weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 2 years; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 4weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 3 years; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 4weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 24hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 48hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 96hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 1week.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 2weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 3weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 4weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 3months.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 6months.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 1year.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 2years.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 3years.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 24 hours; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 24hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 48 hours; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 48hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 96 hours; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 96hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least one week; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 1week.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 2 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 2weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 3 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 3weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 4 weeks; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 4weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 3 months; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 3months.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 6 months; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 6months.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least one year; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about oneyear.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 2 years; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 2years.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising, ina unit dosage form: i) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin or a pharmaceutically-acceptable salt thereof; ii)chlorobutanol; iii) acetic acid; and iv) water; b) storing the unitdosage form at 2-8° C., for example, 5° C., for at least 3 years; c)diluting the unit dosage form in 0.9% saline or 5% dextrose in water toprovide a concentration from about 0.1 units/mL to about 1 unit/mL(about 0.21 μg/mL to about 2.1 μg/mL) of vasopressin or thepharmaceutically-acceptable salt thereof; and d) administering thediluted unit dosage form to the human by intravenous administration;wherein: the administration provides to the human from about 0.01 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute to about 0.1 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute; and the human ishypotensive, wherein the unit dosage form exhibits less than about 5%degradation after storage at 2-8° C., for example, 5° C., for about 3years.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 24 hours; and c) intravenouslyadministering the pharmaceutical composition to the human, wherein theadministration provides to the human from about 0.01 units ofvasopressin or the pharmaceutically-acceptable salt thereof per minuteto about 0.1 units of vasopressin or the pharmaceutically-acceptablesalt thereof per minute; wherein the human is hypotensive, wherein thepharmaceutical composition exhibits less than about 5% degradation afterstorage at 2-8° C., for example, 5° C., for about four weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 48 hours; and c) intravenouslyadministering the pharmaceutical composition to the human, wherein theadministration provides to the human from about 0.01 units ofvasopressin or the pharmaceutically-acceptable salt thereof per minuteto about 0.1 units of vasopressin or the pharmaceutically-acceptablesalt thereof per minute; wherein the human is hypotensive, wherein thepharmaceutical composition exhibits less than about 5% degradation afterstorage at 2-8° C., for example, 5° C., for about four weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 96 hours; and c) intravenouslyadministering the pharmaceutical composition to the human, wherein theadministration provides to the human from about 0.01 units ofvasopressin or the pharmaceutically-acceptable salt thereof per minuteto about 0.1 units of vasopressin or the pharmaceutically-acceptablesalt thereof per minute; wherein the human is hypotensive, wherein thepharmaceutical composition exhibits less than about 5% degradation afterstorage at 2-8° C., for example, 5° C., for about four weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 1 week; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about four weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 2 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about four weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 3 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about four weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 4 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 1 week.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 3 months; and c) intravenouslyadministering the pharmaceutical composition to the human, wherein theadministration provides to the human from about 0.01 units ofvasopressin or the pharmaceutically-acceptable salt thereof per minuteto about 0.1 units of vasopressin or the pharmaceutically-acceptablesalt thereof per minute; wherein the human is hypotensive, wherein thepharmaceutical composition exhibits less than about 5% degradation afterstorage at 2-8° C., for example, 5° C., for about four weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 6 months; and c) intravenouslyadministering the pharmaceutical composition to the human, wherein theadministration provides to the human from about 0.01 units ofvasopressin or the pharmaceutically-acceptable salt thereof per minuteto about 0.1 units of vasopressin or the pharmaceutically-acceptablesalt thereof per minute; wherein the human is hypotensive, wherein thepharmaceutical composition exhibits less than about 5% degradation afterstorage at 2-8° C., for example, 5° C., for about four weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 1 year; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about four weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 2 years; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about four weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 3 years; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about four weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 4 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 24 hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 4 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 48 hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 4 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 96 hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 4 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 1 week.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 4 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about two weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 4 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about three weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 4 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about four weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 4 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 3 months.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 4 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 6 months.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 4 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 1 year.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 4 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 2 years.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 4 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 3 years.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 24 hours; and c) intravenouslyadministering the pharmaceutical composition to the human, wherein theadministration provides to the human from about 0.01 units ofvasopressin or the pharmaceutically-acceptable salt thereof per minuteto about 0.1 units of vasopressin or the pharmaceutically-acceptablesalt thereof per minute; wherein the human is hypotensive, wherein thepharmaceutical composition exhibits less than about 5% degradation afterstorage at 2-8° C., for example, 5° C., for about 24 hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 48 hours; and c) intravenouslyadministering the pharmaceutical composition to the human, wherein theadministration provides to the human from about 0.01 units ofvasopressin or the pharmaceutically-acceptable salt thereof per minuteto about 0.1 units of vasopressin or the pharmaceutically-acceptablesalt thereof per minute; wherein the human is hypotensive, wherein thepharmaceutical composition exhibits less than about 5% degradation afterstorage at 2-8° C. for about, for example, 5° C., 48 hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 96 hours; and c) intravenouslyadministering the pharmaceutical composition to the human, wherein theadministration provides to the human from about 0.01 units ofvasopressin or the pharmaceutically-acceptable salt thereof per minuteto about 0.1 units of vasopressin or the pharmaceutically-acceptablesalt thereof per minute; wherein the human is hypotensive, wherein thepharmaceutical composition exhibits less than about 5% degradation afterstorage at 2-8° C., for example, 5° C., for about 96 hours.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 1 week; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 1 week.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 2 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 2 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 3 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 3 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 4 weeks; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 4 weeks.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 3 months; and c) intravenouslyadministering the pharmaceutical composition to the human, wherein theadministration provides to the human from about 0.01 units ofvasopressin or the pharmaceutically-acceptable salt thereof per minuteto about 0.1 units of vasopressin or the pharmaceutically-acceptablesalt thereof per minute; wherein the human is hypotensive, wherein thepharmaceutical composition exhibits less than about 5% degradation afterstorage at 2-8° C., for example, 5° C., for about 3 months.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 6 months; and c) intravenouslyadministering the pharmaceutical composition to the human, wherein theadministration provides to the human from about 0.01 units ofvasopressin or the pharmaceutically-acceptable salt thereof per minuteto about 0.1 units of vasopressin or the pharmaceutically-acceptablesalt thereof per minute; wherein the human is hypotensive, wherein thepharmaceutical composition exhibits less than about 5% degradation afterstorage at 2-8° C., for example, 5° C., for about 6 months.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 1 year; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 1 year.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 2 years; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 2 years.

The present invention provides a method of increasing blood pressure ina human in need thereof, the method comprising: a) providing apharmaceutical composition for intravenous administration comprising: i)from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or apharmaceutically-acceptable salt thereof; ii) acetic acid; and iii)water; and b) storing the pharmaceutical composition at 2-8° C., forexample, 5° C., for at least 3 years; and c) intravenously administeringthe pharmaceutical composition to the human, wherein the administrationprovides to the human from about 0.01 units of vasopressin or thepharmaceutically-acceptable salt thereof per minute to about 0.1 unitsof vasopressin or the pharmaceutically-acceptable salt thereof perminute; wherein the human is hypotensive, wherein the pharmaceuticalcomposition exhibits less than about 5% degradation after storage at2-8° C., for example, 5° C., for about 3 years.

Dosage Amounts.

In practicing the methods of treatment or use provided herein,therapeutically-effective amounts of the compounds described herein areadministered in pharmaceutical compositions to a subject having adisease or condition to be treated. A therapeutically-effective amountcan vary widely depending on the severity of the disease, the age andrelative health of the subject, the potency of the compounds used, andother factors. Subjects can be, for example, humans, elderly adults,adults, adolescents, pre-adolescents, children, toddlers, infants, orneonates. A subject can be a patient.

Pharmaceutical compositions of the invention can be formulated in anysuitable volume. The formulation volume can be, for example, about 0.1mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.1 mL,about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL,about 1.7 mL, about 1.8 mL, about 1.9 mL, about 2 mL, about 2.1 mL,about 2.2 mL, about 2.3 mL, about 2.4 mL, about 2.5 mL, about 2.6 mL,about 2.7 mL, about 2.8 mL, about 2.9 mL, about 3 mL, about 3.1 mL,about 3.2 mL, about 3.3 mL, about 3.4 mL, about 3.5 mL, about 3.6 mL,about 3.7 mL, about 3.8 mL, about 3.9 mL, about 4 mL, about 4.1 mL,about 4.2 mL, about 4.3 mL, about 4.4 mL, about 4.5 mL, about 4.6 mL,about 4.7 mL, about 4.8 mL, about 4.9 mL, about 5 mL, about 5.1 mL,about 5.2 mL, about 5.3 mL, about 5.4 mL, about 5.5 mL, about 5.6 mL,about 5.7 mL, about 5.8 mL, about 5.9 mL, about 6 mL, about 6.1 mL,about 6.2 mL, about 6.3 mL, about 6.4 mL, about 6.5 mL, about 6.6 mL,about 6.7 mL, about 6.8 mL, about 6.9 mL, about 7 mL, about 7.1 mL,about 7.2 mL, about 7.3 mL, about 7.4 mL, about 7.5 mL, about 7.6 mL,about 7.7 mL, about 7.8 mL, about 7.9 mL, about 8 mL, about 8.1 mL,about 8.2 mL, about 8.3 mL, about 8.4 mL, about 8.5 mL, about 8.6 mL,about 8.7 mL, about 8.8 mL, about 8.9 mL, about 9 mL, about 9.1 mL,about 9.2 mL, about 9.3 mL, about 9.4 mL, about 9.5 mL, about 9.6 mL,about 9.7 mL, about 9.8 mL, about 9.9 mL, about 10 mL, about 11 mL,about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about17 mL, about 18 mL, about 19 mL, or about 20 mL.

A therapeutically-effective amount of a compound described herein can bepresent in a composition at a concentration of, for example, about 0.1units/mL, about 0.2 units/mL, about 0.3 units/mL, about 0.4 units/mL,about 0.5 units/mL, about 0.6 units/mL, about 0.7 units/mL, about 0.8units/mL, about 0.9 units/mL, about 1 unit/mL, about 2 units/mL, about 3units/mL, about 4 units/mL, about 5 units/mL, about 6 units/mL, about 7units/mL, about 8 units/mL, about 9 units/mL, about 10 units/mL, about11 units/mL, about 12 units/mL, about 13 units/mL, about 14 units/mL,about 15 units/mL, about 16 units/mL, about 17 units/mL, about 18units/mL, about 19 units/mL, about 20 units/mL, about 21 units/mL, about22 units/mL, about 23 units/mL, about 24 units/mL about 25 units/mL,about 30 units/mL, about 35 units/mL, about 40 units/mL, about 45units/mL, or about 50 units/mL.

A therapeutically-effective amount of a compound described herein can bepresent in a composition of the invention at a mass of about, forexample, about 0.01 μg, about 0.05 about 0.1 μg, about 0.15 μg, about0.2 μg, about 0.25 about 0.3 about 0.35 about 0.4 about 0.5 μg, about0.6 μg, about 0.7 μg, about 0.8 μg, about 0.9 μg, about 1 μg, about 2μg, about 3 μg, about 4 μg, about 5 μg, about 10 μg, about 15 μg, about20 μg, about 25 μg, about 30 about 35 about 40 μg, about 45 about 50 μg,about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about125 μg, about 150 μg, about 175 about 200 μg, about 250 about 300 μg,about 350 μg, about 400 μg, about 450 μg, about 500 μg, about 600 μg,about 700 μg, about 800 μg, about 900 μg, about 1 mg, about 2 mg, about3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about9 mg, or about 10 mg.

A therapeutically-effective amount of a compound described herein can bepresent in a composition of the invention at a concentration of, forexample, about 0.001 mg/mL, about 0.002 mg/mL, about 0.003 mg/mL, about0.004 mg/mL, about 0.005 mg/mL, about 0.006 mg/mL, about 0.007 mg/mL,about 0.008 mg/mL, about 0.009 mg/mL, about 0.01 mg/mL, about 0.02mg/mL, about 0.03 mg/mL, about 0.04 mg/mL, about 0.05 mg/mL, about 0.06mg/mL, about 0.07 mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, about 0.1mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9mg/mL, about 1 mg/mL, about 1.5 mg/mL, about 2 mg/mL, about 2.5 mg/mL,about 3 mg/mL, about 3.5 mg/mL, about 4 mg/mL, about 4.5 mg/mL, about 5mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, orabout 10 mg/mL.

A therapeutically-effective amount of a compound described herein can bepresent in a composition of the invention at a unit of active agent/unitof active time. Non-limiting examples of therapeutically-effectiveamounts can be, for example, about 0.01 units/minute, about 0.02units/minute, about 0.03 units/minute, about 0.04 units/minute, about0.05 units/minute, about 0.06 units/minute, about 0.07 units/minute,about 0.08 units/minute, about 0.09 units/minute or about 0.1units/minute.

Pharmaceutical compositions of the invention can be formulated at anysuitable pH. The pH can be, for example, about 2, about 2.05, about 2.1,about 2.15, about 2.2, about 2.25, about 2.3, about 2.35, about 2.4,about 2.45, about 2.5, about 2.55, about 2.6, about 2.65, about 2.7,about 2.75, about 2.8, about 2.85, about 2.9, about 2.95, about 3, about3.05, about 3.1, about 3.15, about 3.2, about 3.25, about 3.3, about3.35, about 3.4, about 3.45, about 3.5, about 3.55, about 3.6, about3.65, about 3.7, about 3.75, about 3.8, about 3.85, about 3.9, about3.95, about 4, about 4.05, about 4.1, about 4.15, about 4.2, about 4.25,about 4.3, about 4.35, about 4.4, about 4.45, about 4.5, about 4.55,about 4.6, about 4.65, about 4.7, about 4.75, about 4.8, about 4.85,about 4.9, about 4.95, or about 5 pH units.

Pharmaceutical compositions of the invention can be formulated at anysuitable pH. The pH can be, for example, from about 2 to about 2.2,about 2.05 to about 2.25, about 2.1 to about 2.3, about 2.15 to about2.35, about 2.2 to about 2.4, about 2.25 to about 2.45, about 2.3 toabout 2.5, about 2.35 to about 2.55, about 2.4 to about 2.6, about 2.45to about 2.65, about 2.5 to about 2.7, about 2.55 to about 2.75, about2.6 to about 2.8, about 2.65 to about 2.85, about 2.7 to about 2.9,about 2.75 to about 2.95, about 2.8 to about 3, about 2.85 to about3.05, about 2.9 to about 3.1, about 2.95 to about 3.15, about 3 to about3.2, about 3.05 to about 3.25, about 3.1 to about 3.3, about 3.15 toabout 3.35, about 3.2 to about 3.4, about 3.25 to about 3.45, about 3.3to about 3.5, about 3.35 to about 3.55, about 3.4 to about 3.6, about3.45 to about 3.65, about 3.5 to about 3.7, about 3.55 to about 3.75,about 3.6 to about 3.8, about 3.65 to about 3.85, about 3.7 to about3.9, about 3.7 to about 3.8, about 3.75 to about 3.95, about 3.75 toabout 3.8, about 3.8 to about 3.85, about 3.75 to about 3.85, about 3.8to about 4, about 3.85 to about 4.05, about 3.9 to about 4.1, about 3.95to about 4.15, about 4 to about 4.2, about 4.05 to about 4.25, about 4.1to about 4.3, about 4.15 to about 4.35, about 4.2 to about 4.4, about4.25 to about 4.45, about 4.3 to about 4.5, about 4.35 to about 4.55,about 4.4 to about 4.6, about 4.45 to about 4.65, about 4.5 to about4.7, about 4.55 to about 4.75, about 4.6 to about 4.8, about 4.65 toabout 4.85, about 4.7 to about 4.9, about 4.75 to about 4.95, about 4.8to about 5, about 4.85 to about 5.05, about 4.9 to about 5.1, about 4.95to about 5.15, or about 5 to about 5.2 pH units.

In some embodiments, the addition of an excipient can change theviscosity of a pharmaceutical composition of the invention. In someembodiments the use of an excipient can increase or decrease theviscosity of a fluid by at least 0.001 Pascal-second (Pa.$), at least0.001 Pa·s, at least 0.0009 Pa·s, at least 0.0008 Pa·s, at least 0.0007Pa·s, at least 0.0006 Pa·s, at least 0.0005 Pa·s, at least 0.0004 Pa·s,at least 0.0003 Pa·s, at least 0.0002 Pa·s, at least 0.0001 Pa·s, atleast 0.00005 Pa·s, or at least 0.00001 Pa·s.

In some embodiments, the addition of an excipient to a pharmaceuticalcomposition of the invention can increase or decrease the viscosity ofthe composition by at least 5%, at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least95%, or at least 99%. In some embodiments, the addition of an excipientto a pharmaceutical composition of the invention can increase ordecrease the viscosity of the composition by no greater than 5%, nogreater than 10%, no greater than 15%, no greater than 20%, no greaterthan 25%, no greater than 30%, no greater than 35%, no greater than 40%,no greater than 45%, no greater than 50%, no greater than 55%, nogreater than 60%, no greater than 65%, no greater than 70%, no greaterthan 75%, no greater than 80%, no greater than 85%, no greater than 90%,no greater than 95%, or no greater than 99%.

Any compound herein can be purified. A compound can be at least 1% pure,at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure,at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure,at least 10% pure, at least 11% pure, at least 12% pure, at least 13%pure, at least 14% pure, at least 15% pure, at least 16% pure, at least17% pure, at least 18% pure, at least 19% pure, at least 20% pure, atleast 21% pure, at least 22% pure, at least 23% pure, at least 24% pure,at least 25% pure, at least 26% pure, at least 27% pure, at least 28%pure, at least 29% pure, at least 30% pure, at least 31% pure, at least32% pure, at least 33% pure, at least 34% pure, at least 35% pure, atleast 36% pure, at least 37% pure, at least 38% pure, at least 39% pure,at least 40% pure, at least 41% pure, at least 42% pure, at least 43%pure, at least 44% pure, at least 45% pure, at least 46% pure, at least47% pure, at least 48% pure, at least 49% pure, at least 50% pure, atleast 51% pure, at least 52% pure, at least 53% pure, at least 54% pure,at least 55% pure, at least 56% pure, at least 57% pure, at least 58%pure, at least 59% pure, at least 60% pure, at least 61% pure, at least62% pure, at least 63% pure, at least 64% pure, at least 65% pure, atleast 66% pure, at least 67% pure, at least 68% pure, at least 69% pure,at least 70% pure, at least 71% pure, at least 72% pure, at least 73%pure, at least 74% pure, at least 75% pure, at least 76% pure, at least77% pure, at least 78% pure, at least 79% pure, at least 80% pure, atleast 81% pure, at least 82% pure, at least 83% pure, at least 84% pure,at least 85% pure, at least 86% pure, at least 87% pure, at least 88%pure, at least 89% pure, at least 90% pure, at least 91% pure, at least92% pure, at least 93% pure, at least 94% pure, at least 95% pure, atleast 96% pure, at least 97% pure, at least 98% pure, at least 99% pure,at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7%pure, at least 99.8% pure, or at least 99.9% pure.

Compositions of the invention can be packaged as a kit. In someembodiments, a kit includes written instructions on the administrationor use of the composition. The written material can be, for example, alabel. The written material can suggest conditions methods ofadministration. The instructions provide the subject and the supervisingphysician with the best guidance for achieving the optimal clinicaloutcome from the administration of the therapy. In some embodiments, thelabel can be approved by a regulatory agency, for example the U.S. Foodand Drug Administration (FDA), the European Medicines Agency (EMA), orother regulatory agencies.

A composition described herein can be provided as a pharmaceuticalformulation that can be stored in, for example, a vial or a container.The vial or container can contain, at the opening, a dispensing regionfrom which a portion of the pharmaceutical formulation can be withdrawnfor administration to a subject. In some embodiments, the dispensingregion is punctured by, for example, a hypodermic needle to access thepharmaceutical formulation. The dispensing region can be punctured, forexample, one time, two times, three times, four times, five times, sixtimes, seven time, eight time, nine times, ten times, 11 times, 12times, 13 times, 14 times, 15 times, or as many times as needed fortreatment of the subject. The dispensing region can be made of, forexample, aluminum, rubber, plastic, wax, or any combination thereof.

The dispensing region of the contain can be punctured within one hour,two hours, three hours, four hours, five hours, six hours, seven hours,eight hours, nine hours, ten hours, 11 hours, 12 hours, one day (24hours), two days (48 hours), three days, four days, five days, six days,one week, two weeks, three weeks, one month (30 days), two months, threemonths, four months, five months, six months, seven months, eightmonths, nine months, ten months, eleven months, or one year from thefirst puncture of the dispensing region of the container.

Pharmaceutically-acceptable excipients.

Non-limiting examples of pharmaceutically-acceptable excipients can befound, for example, in Remington: The Science and Practice of Pharmacy,Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, JohnE., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999), each of which is incorporated by reference in itsentirety.

In some embodiments, the pharmaceutical composition provided hereincomprises a sugar as an excipient. Non-limiting examples of sugarsinclude trehalose, sucrose, glucose, lactose, galactose, glyceraldehyde,fructose, dextrose, maltose, xylose, mannose, maltodextrin, starch,cellulose, lactulose, cellobiose, mannobiose, and combinations thereof.

In some embodiments, the pharmaceutical composition provided hereincomprises a buffer as an excipient. Non-limiting examples of buffersinclude potassium phosphate, sodium phosphate, saline sodium citratebuffer (SSC), acetate, saline, physiological saline, phosphate buffersaline (PBS), 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer(HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), andpiperazine-N,N′-bis(2-ethanesulfonic acid) buffer (PIPES), orcombinations thereof.

In some embodiments, a pharmaceutical composition of the inventioncomprises a source of divalent metal ions as an excipient. A metal canbe in elemental form, a metal atom, or a metal ion. Non-limitingexamples of metals include transition metals, main group metals, andmetals of Group 1, Group 2, Group 3, Group 4, Group 5, Group 6, Group 7,Group 8, Group 9, Group 10, Group 11, Group 12, Group 13, Group 14, andGroup 15 of the Periodic Table. Non-limiting examples of metals includelithium, sodium, potassium, cesium, magnesium, calcium, strontium,scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel,copper, zinc, yttrium, zirconium, niobium, molybdenum, palladium,silver, cadmium, tungsten, rhenium, osmium, iridium, platinum, gold,mercury, cerium, and samarium.

In some embodiments, the pharmaceutical composition provided hereincomprises an alcohol as an excipient. Non-limiting examples of alcoholsinclude ethanol, propylene glycol, glycerol, polyethylene glycol,chlorobutanol, isopropanol, xylitol, sorbitol, maltitol, erythritol,threitol, arabitol, ribitol, mannitol, galactilol, fucitol, lactitol,and combinations thereof.

Pharmaceutical preparations can be formulated with polyethylene glycol(PEG). PEGs with molecular weights ranging from about 300 g/mol to about10,000,000 g/mol can be used. Non-limiting examples of PEGs include PEG200, PEG 300, PEG 400, PEG 540, PEG 550, PEG 600, PEG 1000, PEG 1450,PEG 1500, PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 4600, PEG 6000,PEG 8000, PEG 10,000, and PEG 20,000.

Further excipients that can be used in a composition of the inventioninclude, for example, benzalkonium chloride, benzethonium chloride,benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene,chlorobutanol, dehydroacetic acid, ethylenediamine, ethyl vanillin,glycerin, hypophosphorous acid, phenol, phenylethyl alcohol,phenylmercuric nitrate, potassium benzoate, potassium metabisulfite,potassium sorbate, sodium bisulfite, sodium metabisulfite, sorbic acid,thimerasol, acetic acid, aluminum monostearate, boric acid, calciumhydroxide, calcium stearate, calcium sulfate, calcium tetrachloride,cellulose acetate pthalate, microcrystalline celluose, chloroform,citric acid, edetic acid, and ethylcellulose.

In some embodiments, the pharmaceutical composition provided hereincomprises an aprotic solvent as an excipient. Non-limiting examples ofaprotic solvents include perfluorohexane, α,α,α-trifluorotoluene,pentane, hexane, cyclohexane, methylcyclohexane, decalin, dioxane,carbon tetrachloride, freon-11, benzene, toluene, carbon disulfide,diisopropyl ether, diethyl ether, t-butyl methyl ether, ethyl acetate,1,2-dimethoxyethane, 2-methoxyethyl ether, tetrahydrofuran, methylenechloride, pyridine, 2-butanone, acetone, N-methylpyrrolidinone,nitromethane, dimethylformamide, acetonitrile, sulfolane, dimethylsulfoxide, and propylene carbonate.

The amount of the excipient in a pharmaceutical composition of theinvention can be about 0.01%, about 0.02%, about 0.03%, about 0.04%,about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%,about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%,about 70%, about 80%, about 90%, about 100%, about 200%, about 300%,about 400%, about 500%, about 600%, about 700%, about 800%, about 900%,or about 1000% by mass of the vasopressin in the pharmaceuticalcomposition.

The amount of the excipient in a pharmaceutical composition of theinvention can be about 0.01%, about 0.02%, about 0.03%, about 0.04%,about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%,about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about90%, about 95%, about 99%, or about 100% by mass or by volume of theunit dosage form.

The ratio of vasopressin to an excipient in a pharmaceutical compositionof the invention can be about 100:about 1, about 95:about 1, about90:about 1, about 85:about 1, about 80:about 1, about 75:about 1, about70:about 1, about 65:about 1, about 60:about 1, about 55:about 1, about50:about 1, about 45:about 1, about 40:about 1, about 35:about 1 about30:about 1, about 25:about 1, about 20:about 1, about 15:about 1, about10:about 1, about 9:about 1, about 8:about 1, about 7:about 1, about6:about 1, about 5:about 1, about 4:about 1, about 3:about 1, about2:about 1, about 1:about 1, about 1:about 2, about 1:about 3, about1:about 4, about 1:about 5, about 1:about 6, about 1:about 7, about1:about 8, about 1:about 9, or about 1:about 10.

Pharmaceutically Acceptable Salts.

The invention provides the use of pharmaceutically-acceptable salts ofany therapeutic compound described herein. Pharmaceutically-acceptablesalts include, for example, acid-addition salts and base-addition salts.The acid that is added to the compound to form an acid-addition salt canbe an organic acid or an inorganic acid. A base that is added to thecompound to form a base-addition salt can be an organic base or aninorganic base. In some embodiments, a pharmaceutically-acceptable saltis a metal salt. In some embodiments, a pharmaceutically-acceptable saltis an ammonium salt.

Metal salts can arise from the addition of an inorganic base to acompound of the invention. The inorganic base consists of a metal cationpaired with a basic counterion, such as, for example, hydroxide,carbonate, bicarbonate, or phosphate. The metal can be an alkali metal,alkaline earth metal, transition metal, or main group metal. In someembodiments, the metal is lithium, sodium, potassium, cesium, cerium,magnesium, manganese, iron, calcium, strontium, cobalt, titanium,aluminum, copper, cadmium, or zinc.

In some embodiments, a metal salt is a lithium salt, a sodium salt, apotassium salt, a cesium salt, a cerium salt, a magnesium salt, amanganese salt, an iron salt, a calcium salt, a strontium salt, a cobaltsalt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt,or a zinc salt.

Ammonium salts can arise from the addition of ammonia or an organicamine to a compound of the invention. In some embodiments, the organicamine is triethyl amine, diisopropyl amine, ethanol amine, diethanolamine, triethanol amine, morpholine, N-methylmorpholine, piperidine,N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine,pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine.

In some embodiments, an ammonium salt is a triethyl amine salt, adiisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, atriethanol amine salt, a morpholine salt, an N-methylmorpholine salt, apiperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt,a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazolesalt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, or apipyrazine salt.

Acid addition salts can arise from the addition of an acid to a compoundof the invention. In some embodiments, the acid is organic. In someembodiments, the acid is inorganic. In some embodiments, the acid ishydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid,nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid,isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbicacid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid,formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid,propionic acid, butyric acid, fumaric acid, succinic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

In some embodiments, the salt is a hydrochloride salt, a hydrobromidesalt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfatesalt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactatesalt, a salicylate salt, a tartrate salt, an ascorbate salt, agentisinate salt, a gluconate salt, a glucaronate salt, a saccaratesalt, a formate salt, a benzoate salt, a glutamate salt, a pantothenatesalt, an acetate salt, a propionate salt, a butyrate salt, a fumaratesalt, a succinate salt, a methanesulfonate (mesylate) salt, anethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonatesalt, a citrate salt, an oxalate salt, or a maleate salt.

Peptide Sequence.

As used herein, the abbreviations for the L-enantiomeric andD-enantiomeric amino acids are as follows: alanine (A,Ala); arginine (R,Arg); asparagine (N, Asn); aspartic acid (D, Asp); cysteine (C, Cys);glutamic acid (E, Glu); glutamine (Q, Gln); glycine (G, Gly); histidine(H, His); isoleucine (I, Ile); leucine (L, Leu); lysine (K, Lys);methionine (M, Met); phenylalanine (F, Phe); proline (P, Pro); serine(S, Ser); threonine (T, Thr); tryptophan (W, Trp); tyrosine (Y, Tyr);valine (V, Val). In some embodiments, the amino acid is a L-enantiomer.In some embodiments, the amino acid is a D-enantiomer.

A peptide of the disclosure can have about 5%, about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%,about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, orabout 100% amino acid sequence homology to SEQ ID NO. 1.

In some embodiments, a pharmaceutical composition of the inventioncomprises one or a plurality of peptides having about 80% to about 90%sequence homology to SEQ ID NO. 1, about 88% to about 90% sequencehomology to SEQ ID NO. 1 or 88% to 90% sequence homology to SEQ IDNO. 1. In some embodiments, a pharmaceutical composition of theinvention comprises vasopressin and one or more of a second, third,fourth, fifth, sixth, seventh, eighth, ninth, and tenth peptide.

The ratio of vasopressin to another peptide in a pharmaceuticalcomposition of the invention can be, for example, about 1000:about 1,about 990:about 1, about 980:about 1, about 970:about 1, about 960:about1, about 950:about 1, about 800:about 1, about 700:about 1, about 600:1,about 500:about 1, about 400:about 1, about 300:about 1, about 200:about1, about 100:about 1, about 95:about 1, about 90:about 1, about 85:about1, about 80:about 1, about 75:about 1, about 70:about 1, about 65:about1, about 60:about 1, about 55:about 1, about 50:about 1, about 45:about1, about 40:about 1, about 35:about 1, about 30:about 1, about 25:about1, about 20:about 1, about 19:about 1, about 18:about 1, about 17:about1, about 16:about 1, about 15:about 1, about 14:about 1, about 13:about1, about 12:about 1, about 11:about 1, or about 10:about 1.

The amount of another peptide or impurity in a composition of theinvention can be, for example, about 0.01%, about 0.02%, about 0.03%,about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about4.8%, about 4.9%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%,about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%,about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%,about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% bymass of vasopressin.

Another peptide or impurity present in a composition described hereincan be, for example, SEQ ID NO.: 2, SEQ ID NO.: 3, SEQ ID NO.: 4, SEQ IDNO.: 5, SEQ ID NO.: 6, SEQ ID NO.: 7, SEQ ID NO.: 8, SEQ ID NO.: 9, SEQID NO.: 10, SEQ ID NO.: 11, SEQ ID NO.: 12, SEQ ID NO.: 13, SEQ ID NO.:14, SEQ ID NO.: 15, SEQ ID NO.: 16, SEQ ID NO.: 17, a dimer of SEQ IDNO.: 1, an unidentified impurity, or any combination thereof.

Non-limiting examples of methods that can be used to identify peptidesof the invention include high-performance liquid chromatography (HPLC),mass spectrometry (MS), Matrix Assisted Laser Desorption IonizationTime-of-Flight (MALDI-TOF), electrospray ionization Time-of-flight(ESI-TOF), gas chromatography-mass spectrometry (GC-MS), liquidchromatography-mass spectrometry (LC-MS), and two-dimensional gelelectrophoresis.

HPLC can be used to identify peptides using high pressure to separatecomponents of a mixture through a packed column of solid adsorbentmaterial, denoted the stationary phase. The sample components caninteract differently with the column based upon the pressure applied tothe column, material used in stationary phase, size of particles used inthe stationary phase, the composition of the solvent used in the column,and the temperature of the column. The interaction between the samplecomponents and the stationary phase can affect the time required for acomponent of the sample to move through the column. The time requiredfor component to travel through the column from injection point toelution is known as the retention time.

Upon elution from the column, the eluted component can be detected usinga UV detector attached to the column. The wavelength of light at whichthe component is detected, in combination with the component's retentiontime, can be used to identify the component. Further, the peak displayedby the detector can be used to determine the quantity of the componentpresent in the initial sample. Wavelengths of light that can be used todetect sample components include, for example, about 200 nM, about 225nm, about 250 nm, about 275 nm, about 300 nm, about 325 nm, about 350nm, about 375 nm, and about 400 nm.

Mass spectrometry (MS) can also be used to identify peptides of theinvention. To prepare samples for MS analysis, the samples, containingthe proteins of interest, are digested by proteolytic enzymes intosmaller peptides. The enzymes used for cleavage can be, for example,trypsin, chymotrypsin, glutamyl endopeptidase, Lys-C, and pepsin. Thesamples can be injected into a mass spectrometer. Upon injection, all ormost of the peptides can be ionized and detected as ions on a spectrumaccording to the mass to charge ratio created upon ionization. The massto charge ratio can then be used to determine the amino acid residuespresent in the sample.

The present disclosure provides several embodiments of pharmaceuticalformulations that provide advantages in stability, administration,efficacy, and modulation of formulation viscosity. Any embodimentsdisclosed herein can be used in conjunction or individually. Forexample, any pharmaceutically-acceptable excipient, method, technique,solvent, compound, or peptide disclosed herein can be used together withany other pharmaceutically-acceptable excipient, method, technique,solvent, compound, or peptide disclosed herein to achieve anytherapeutic result. Compounds, excipients, and other formulationcomponents can be present at any amount, ratio, or percentage disclosedherein in any such formulation, and any such combination can be usedtherapeutically for any purpose described herein and to provide anyviscosity described herein.

EXAMPLES Example 1: Impurities of Vasopressin as Detected by HPLC

To analyze degradation products of vasopressin that can be present in anillustrative formulation of vasopressin, gradient HPLC was performed toseparate vasopressin from related peptides and formulation components.TABLE 2 below depicts the results of the experiment detailing thechemical formula, relative retention time (RRT), molar mass, andstructure of vasopressin and detected impurities.

Vasopressin was detected in the eluent using UV absorbance. Theconcentration of vasopressin in the sample was determined by theexternal standard method, where the peak area of vasopressin in sampleinjections was compared to the peak area of vasopressin referencestandards in a solution of known concentration. The concentrations ofrelated peptide impurities in the sample were also determined using theexternal standard method, using the vasopressin reference standard peakarea and a unit relative response factor. An impurities marker solutionwas used to determine the relative retention times of identified relatedpeptides at the time of analysis.

Experimental conditions are summarized in TABLE 2 below.

TABLE 2 Column YMC-Pack ODS-AM, 3 μm, 120 Å pore, 4.6 × 100 mm ColumnTemperature 25° C. Flow Rate 1.0 mL/min Detector 215 nm Note: ForIdentification a Diode Array Detector (DAD) was used with the range of200-400 nm. Injection Volume 100 μL Run time 55 minutes AutosamplerVials Polypropylene vials Time (min) % A % B Flow Pump (gradient) 0 9010 1.0 40 50 50 1.0 45 50 50 1.0 46 90 10 1.0 55 90 10 1.0

The diluent used for the present experiment was 0.25% v/v Acetic Acid,which was prepared by transferring 2.5 mL of glacial acetic acid into a1-L volumetric flask containing 500 mL of water. The solution wasdiluted to the desired volume with water.

Phosphate buffer at pH 3.0 was used for mobile phase A. The buffer wasprepared by weighing approximately 15.6 g of sodium phosphate monobasicmonohydrate into a beaker. 1000 mL of water was added, and mixed well.The pH was adjusted to 3.0 with phosphoric acid. The buffer was filteredthrough a 0.45 μm membrane filter under vacuum, and the volume wasadjusted as necessary.

An acetonitrile:water (50:50) solution was used for mobile phase B. Toprepare mobile phase B, 500 mL of acetonitrile was mixed with 500 mL ofwater.

The working standard solution contained approximately 20 units/mL ofvasopressin. The standard solution was prepared by quantitativelytransferring the entire contents of 1 vial of USP Vasopressin RS withdiluent to a 50-mL volumetric flask.

The intermediate standard solution was prepared by pipetting 0.5 mL ofthe working standard solution into a 50-mL volumetric flask.

The sensitivity solution was prepared by pipetting 5.0 mL of theintermediate standard solution into a 50-mL volumetric flask. Thesolution was diluted to the volume with Diluent and mixed well.

A second working standard solution was prepared as directed under thestandard preparation.

A portion of the vasopressin control sample was transferred to an HPLCvial and injected. The control was stable for 120 hours when stored inautosampler vials at ambient laboratory conditions.

To prepare the impurities marker solution, a 0.05% v/v acetic acidsolution was prepared by pipetting 200.0 mL of a 0.25% v/v acetic acidsolution into a 1-L volumetric flask. The solution was diluted to thedesired volume with water and mixed well.

To prepare the vasopressin impurity stock solutions, the a solution ofeach impurity was prepared in a 25 mL volumetric flask and diluted with0.05% v/v acetic acid to a concentration suitable for HPLC injection.

To prepare the MAA/H-IBA (Methacrylic Acid/α-Hydroxy-isobutyric acid)stock solution, a stock solution containing approximately 0.3 mg/mLH-IBA and 0.01 mg/mL in 0.05% v/v acetic acid was made in a 50 mLvolumetric flask.

To prepare the chlorobutanol diluent, about one gram of hydrouschlorobutanol was added to 500 mL of water. Subsequently, 0.25 mL ofacetic acid was added and the solution was stirred to dissolve thechlorobutanol.

To prepare the impurity marker solution, vasopressin powder was mixedwith the impurity stock solutions prepared above.

The solutions were diluted to volume with the chlorobutanol diluent. Thesolutions were aliquoted into individual crimp top vials and stored at2-8° C. At time of use, the solutions were removed from refrigeration(2-8° C.) and allowed to reach room temperature.

The vasopressin impurity marker solution was stable for at least 120hours when stored in auto-sampler vials at ambient laboratoryconditions. The solution was suitable for use as long as thechromatographic peaks could be identified based on comparison to thereference chromatogram.

To begin the analysis, the HPLC system was allowed to equilibrate for atleast 30 minutes using mobile phase B, followed by time 0 min gradientconditions until a stable baseline was achieved.

The diluent was injected at the beginning of the run, and had no peaksthat interfered with Vasopressin at around 18 minutes as shown in FIG.1.

A single injection of the sensitivity solution was performed, whereinthe signal-to-noise ratio of the Vasopressin was greater than or equalto ten as shown in FIG. 2.

A single injection of the impurities marker solution was then made. Thelabeled impurities in the reference chromatogram were identified in thechromatogram of the marker solution based on their elution order andapproximate retention times shown in FIG. 3 and FIG. 4. FIG. 4 is azoomed in chromatograph of FIG. 3 showing the peaks that eluted between15 and 30 minutes. The nomenclature, structure, and approximateretention times for individual identified impurities are detailed inTABLE 3.

A single injection of the working standard solution was made to ensurethat the tailing factor of the vasopressin peak was less than or equalto about 2.0 as shown in FIG. 5.

A total of five replicate injections of the working standard solutionwere made to ensure that the relative standard deviation (% RSD) of thefive replicate vasopressin peak areas was not more than 2.0%.

Two replicate injections of the check standard preparation were toconfirm that the check standard conformity was 99.0%-101.0%. Oneinjection of the control sample was made to confirm that the assay ofthe control sample met the control limits established for the sample.

Then, one injection of the working standard solution was made.

Following the steps above done to confirm system suitability, a singleinjection of each sample preparation was made. The chromatograms wereanalyzed to determine the vasopressin and impurity peak areas. Thechromatogram is depicted in FIG. 6.

The working standard solution was injected after 1 to 4 sampleinjections, and the bracketing standard peak areas were averaged for usein the calculations to determine peak areas of vasopressin andassociated impurities.

The relative standard deviation (% RSD) of vasopressin peak areas forthe six injections of working standard solution was calculated byincluding the initial five injections from the system suitability stepsabove and each of the subsequent interspersed working standard solutioninjections. The calculations were done to ensure that each of the % RSDwere not more than 2.0%.

The retention time of the major peak in the chromatogram of the samplepreparation corresponded to that of the vasopressin peak in the workingstandard solution injection that preceded the sample preparationinjection.

The UV spectrum (200-400 nm) of the main peak in the chromatogram of thesample preparation compared to the UV spectrum of vasopressin in theworking standard preparation. FIG. 7 depicts a UV spectrum of avasopressin sample and FIG. 8 depicts a UV spectrum of vasopressinstandard.

To calculate the vasopressin units/mL, the following formula was used:

${{Vasopressin}{\mspace{11mu} \;}{units}\text{/}{mL}} = {\frac{R_{U}}{R_{S}} \times {Conc}\mspace{11mu} {STD}}$

where:

-   -   R_(U)=Vasopressin peak area response of Sample preparation.    -   R_(S)=average vasopressin peak area response of bracketing        standards.    -   Conc STD=concentration of the vasopressin standard in units/mL

To identify the impurities, the % Impurity and identity for identifiedimpurities (TABLE 3) that are were greater than or equal to 0.10% werereported. Impurities were truncated to 3 decimal places and then roundedto 2 decimal places, unless otherwise specified.

The impurities were calculated using the formula below:

${\% \mspace{14mu} {impurity}} = {\frac{R_{I}}{R_{S}} \times \frac{{Conc}\mspace{11mu} {STD}}{20\mspace{14mu} U\text{/}{mL}} \times 100\%}$

where:

-   -   R_(I)=Peak area response for the impurity    -   20 U/mL=Label content of vasopressin

TABLE 3 below details the chemical formula, relative retention time (RRTin minutes), molar mass, and structure of vasopressin and detectedimpurities.

TABLE 3 Appr. Molar Name Formula RRT Mass (g) Vasopressin C₄₆H₆₅N₁₅O₁₂S₂1.00 1084.23 (Arginine Vasopressin, AVP) CYFQNCPRG-NH₂ SEQ ID NO.: 1(disulfide bridge between cys residues) Gly9-vasopressin C₄₆H₆₄N₁₄O₁₃S₂1.07 1085.22 (Gly9-AVP) CYFQNCPRG SEQ ID NO.: 2 (disulfide bridgebetween cys residues) Asp5-vasopressin C₄₆H₆₄N₁₄O₁₃S₂ 1.09 1085.22(Asp5-AVP) CYFQDCPRG-NH₂ SEQ ID NO.: 3 (disulfide bridge between cysresidues) Glu4-vasopressin C₄₆H₆₄N₁₄O₁₃S₂ 1.12 1085.22 (Glu4-AVP)CYFENCPRG-NH₂ SEQ ID NO.: 4 (disulfide bridge between cys residues)Acetyl-vasopressin C₄₈H₆₇N₁₅O₁₃S₂ 1.45 1126.27 (Acetyl-AVP)Ac-CYFQNCPRG-NH₂ SEQ ID NO.: 7 (disulfide bridge between cys residues)D-Asn-vasopressin C₄₆H₆₅N₁₅O₁₂S₂ 0.97 1084.23 (DAsn-AVP)CYFQ(D-Asn)CPRG-NH₂ SEQ ID NO.: 10 (disulfide bridge between cysresidues) Dimeric-vasopressin C₉₂H₁₃₀N₃₀O₂₄S₄ 1.22 2168.46 (Dimer-AVP)(monomers cross linked by disulfide bridges)

Example 2: Investigation of pH

To determine a possible pH for a vasopressin formulation with good shelflife, vasopressin formulations were prepared in 10 mM citrate bufferdiluted in isotonic saline across a range of pH. Stability was assessedvia HPLC as in EXAMPLE 1 after incubation of the formulations at 60° C.for one week. FIG. 9 illustrates the results of the experiment. Thegreatest level of stability was observed at pH 3.5. At pH 3.5, thepercent label claim (% LC) of vasopressin was highest, and theproportion of total impurities was lowest.

Example 3: Effect of Peptide Stabilizers on Vasopressin Formulation

To observe the effect of stabilizers on the degradation of vasopressin,a series of peptide stabilizers were added to a vasopressin formulationas detailed in TABLE 4. Stability of vasopressin was assessed via HPLCafter incubation of the formulations at 60° C. for one week.

TABLE 4 PEG Poloxamer n-Methylpyrrolidone Ethanol 400 Glycerol 188HPbCD^(a) (NMP)  1%  1%  1%  1%  1%  1% 10% 10% 10% 10% 10% 10%^(a)Hydroxypropyl beta-Cyclodextrin

FIG. 10 illustrates the stability of vasopressin in terms of % labelclaim at varying concentrations of stabilizer. The results indicate thatthe tested stabilizers provided a greater stabilizing effect at 1%concentration than at 10%. Also, in several cases the stabilizationeffect was about 5% to about 10% greater than that observed in theexperiments of EXAMPLE 2.

Example 4: Effect of Buffer and Divalent Metals on VasopressinFormulation

To determine whether different combinations of buffers and use ofdivalent metals affect vasopressin stability, vasopressin formulationswith varying concentrations of citrate and acetate buffers and variableconcentrations of calcium, magnesium, and zinc ions were prepared.Solutions of 0 mM, 10 mM, 20 mM, and 80 mM calcium, magnesium, and zincwere prepared and each was combined with 1 mM or 10 mM of citrate oracetate buffers to test vasopressin stability.

The tested combinations provided vasopressin stability comparable tothat of a vasopressin formulation lacking buffers and divalent metals.However, that the addition of divalent metal ions was able to counteractthe degradation of vasopressin caused by the use of a citrate buffer.

Example 5: Illustrative Formulations for Assessment of VasopressinStability

An aqueous formulation of vasopressin is prepared using 10% trehalose,1% sucrose, or 5% NaCl and incubated at 60° C. for one week, at whichpoint stability of vasopressin is assessed using HPLC.

A formulation containing 50 units of vasopressin is lyophilized. Thelyophilate is reconstituted with water and either 100 mg of sucrose or100 mg of lactose, and the stability of vasopressin is tested via HPLCafter incubation at 60° C. for one week.

Co-solvents are added to a vasopressin solution to assess vasopressinstability. 95% solvent/5% 20 mM acetate buffer solutions are preparedusing propylene glycol, DMSO, PEG300, NMP, glycerol, and glycerol:NMP(1:1), and used to create formulations of vasopressin. The stability ofvasopressin is tested after incubation at 60° C. for one week.

Amino acid and phosphate buffers are tested with vasopressin to assessvasopressin stability. Buffers of 10 mM glycine, aspartate, phosphateare prepared at pH 3.5 and 3.8 and used to create formulations ofvasopressin. The stability of vasopressin is tested after incubation at60° C. for one week.

A vasopressin formulation in 10% polyvinylpyrrolidone is prepared toassess vasopressin stability. The stability of vasopressin will betested after incubation at 60° C. for one week.

A vasopressin formulation that contains 0.9% saline, 10 mM acetatebuffer, 0.2 unit/mL API/mL in 100 mL of total volume is prepared. The pHof the solution is varied from pH 3.5-3.8 to test the stability ofvasopressin.

A vasopressin formulation in about 50% to about 80% DMSO (for example,about 80%), about 20% to about 50% ethyl acetate (for example, about20%), and about 5% to about 30% polyvinylpyrrolidone (PVP) (for example,about 10% by mass of the formulation) is prepared to assess vasopressinstability. PVP K12 and PVP K17 are each independently tested in theformulation. The stability of vasopressin is tested after incubation at60° C. for one week.

A vasopressin formulation in about 70% to about 95% ethyl acetate, andabout 5% to about 30% PVP is prepared to assess vasopressin stability.PVP K12 and PVP K17 are each independently tested in the formulation.The stability of vasopressin is tested after incubation at 60° C. forone week.

A vasopressin formulation in 90% DMSO and 10% PVP is prepared to testvasopressin stability. PVP K12 and PVP K17 are each independently testedin the formulation. The stability of vasopressin is tested afterincubation at 60° C. for one week.

Example 6: Illustrative Vasopressin Formulation for Clinical Use

A formulation for vasopressin that can be used in the clinic is detailedin TABLE 5 below:

TABLE 5 Ingredient Function Amount (per mL) Vasopressin, USP Active 20Units (~0.04 mg) Ingredient Chlorobutanol, Hydrous NF Preservative 5.0mg Acetic Acid, NF pH Adjustment To pH 3.4-3.6 (~0.22 mg) Water forinjection, Diluent QS USP/EP

Example 7: Illustrative Regimen for Therapeutic Use of a VasopressinFormulation

Vasopressin is indicated to increase blood pressure in adults withvasodilatory shock (for example, adults who are post-cardiotomy orseptic) who remain hypotensive despite fluids and catecholamines.

Preparation and Use of Vasopressin.

Vasopressin is supplied in a carton of 25 multi-dose vials eachcontaining 1 mL vasopressin at 20 units/mL.

Vasopressin is stored between 15° C. and 25° C. (59° F. and 77° F.), andis not frozen. Alternatively, a unit dosage form of vasopressin can bestored between 2° C. and 8° C. for about 1 week, 2 weeks, 3 weeks, 4weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks.

Vials of vasopressin are to be discarded 48 hours after first puncture.

Vasopressin is prepared according to TABLE 6 below:

TABLE 6 Mix Fluid Restriction? Final Concentration Vasopressin DiluentNo 0.1 units/mL 2.5 mL (50 units) 500 mL Yes 1 unit/mL 5 mL (100 units)100 mL

Vasopressin is diluted in normal saline (0.9% sodium chloride) or 5%dextrose in water (D5W) prior to use to either 0.1 units/mL or 1 unit/mLfor intravenous administration. Unused diluted solution is discardedafter 18 hours at room temperature or after 24 hours underrefrigeration.

Diluted vasopressin should be inspected for particulate matter anddiscoloration prior to use whenever solution and container permit.

The goal of treatment with vasopressin is optimization of perfusion tocritical organs, but aggressive treatment can compromise perfusion oforgans, like the gastrointestinal tract, for which function is difficultto monitor. Titration of vasopressin to the lowest dose compatible witha clinically-acceptable response is recommended.

For post-cardiotomy shock, a dose of 0.03 units/minute is used as astarting point. For septic shock, a dose of 0.01 units/minute isrecommended. If the target blood pressure response is not achieved,titrate up by 0.005 units/minute at 10- to 15-minute intervals. Themaximum dose for post-cardiotomy shock is 0.1 units/minute and forseptic shock 0.07 units/minute. After target blood pressure has beenmaintained for 8 hours without the use of catecholamines, tapervasopressin by 0.005 units/minute every hour as tolerated to maintaintarget blood pressure.

Vasopressin is provided at 20 units per mL of diluent, which is packagedas 1 mL of vasopressin per vial, and is diluted prior to administration.

Contraindications, Adverse Reactions, and Drug-Drug Interactions.

Vasopressin is contraindicated in patients with known allergy orhypersensitivity to 8-L-arginine vasopressin or chlorobutanol.Additionally, use of vasopressin in patients with impaired cardiacresponse can worsen cardiac output.

Adverse reactions have been observed with the use of vasopressin, whichadverse reactions include bleeding/lymphatic system disorders,specifically, hemorrhagic shock, decreased platelets, intractablebleeding; cardiac disorders, specifically, right heart failure, atrialfibrillation, bradycardia, myocardial ischemia; gastrointestinaldisorders, specifically, mesenteric ischemia; hepatobiliary disorders,specifically, increased bilirubin levels; renal/urinary disorders,specifically, acute renal insufficiency; vascular disorders,specifically, distal limb ischemia; metabolic disorders, specifically,hyponatremia; and skin disorders, specifically, and ischemic lesions.

These reactions are reported voluntarily from a population of uncertainsize. Thus, reliable estimation of frequency or establishment of acausal relationship to drug exposure is unlikely.

Vasopressin has been observed to interact with other drugs. For example,use of vasopressin with catecholamines is expected to result in anadditive effect on mean arterial blood pressure and other hemodynamicparameters. Use of vasopressin with indomethacin can prolong the effectof vasopressin on cardiac index and systemic vascular resistance.Indomethacin more than doubles the time to offset for vasopressin'seffect on peripheral vascular resistance and cardiac output in healthysubjects.

Further, use of vasopressin with ganglionic blocking agents can increasethe effect of vasopressin on mean arterial blood pressure. Theganglionic blocking agent tetra-ethylammonium increases the pressoreffect of vasopressin by 20% in healthy subjects.

Use of vasopressin with furosemide increases the effect of vasopressinon osmolar clearance and urine flow. Furosemide increases osmolarclearance 4-fold and urine flow 9-fold when co-administered withexogenous vasopressin in healthy subjects.

Use of vasopressin with drugs suspected of causing SIADH (Syndrome ofinappropriate antidiuretic hormone secretion), for example, SSRIs,tricyclic antidepressants, haloperidol, chlorpropamide, enalapril,methyldopa, pentamidine, vincristine, cyclophosphamide, ifosfamide, andfelbamate can increase the pressor effect in addition to theantidiuretic effect of vasopressin. Additionally, use of vasopressinwith drugs suspected of causing diabetes insipidus for example,demeclocycline, lithium, foscarnet, and clozapine can decrease thepressor effect in addition to the antidiuretic effect of vasopressin.

Halothane, morphine, fentanyl, alfentanyl and sufentanyl do not impactexposure to endogenous vasopressin.

Use of Vasopressin in Specific Populations.

Vasopressin is a Category C drug for pregnancy.

Due to a spillover into the blood of placental vasopressinase, theclearance of exogenous and endogenous vasopressin increases graduallyover the course of a pregnancy. During the first trimester of pregnancythe clearance is only slightly increased. However, by the thirdtrimester the clearance of vasopressin is increased about 4-fold and atterm up to 5-fold. Due to the increased clearance of vasopressin in thesecond and third trimester, the dose of vasopressin can be up-titratedto doses exceeding 0.1 units/minute in post-cardiotomy shock and 0.07units/minute in septic shock. Vasopressin can produce tonic uterinecontractions that could threaten the continuation of pregnancy. Afterdelivery, the clearance of vasopressin returns to preconception levels.

Overdosage.

Overdosage with vasopressin can be expected to manifest as a consequenceof vasoconstriction of various vascular beds, for example, theperipheral, mesenteric, and coronary vascular beds, and as hyponatremia.In addition, overdosage of vasopressin can lead less commonly toventricular tachyarrhythmias, including Torsade de Pointes,rhabdomyolysis, and non-specific gastrointestinal symptoms. Directeffects of vasopressin overdose can resolve within minutes of withdrawalof treatment.

Pharmacology of Vasopressin.

Vasopressin is a polypeptide hormone that causes contraction of vascularand other smooth muscles and antidiuresis, which can be formulated as asterile, aqueous solution of synthetic arginine vasopressin forintravenous administration. The 1 mL solution contains vasopressin 20units/mL, chlorobutanol, NF 0.5% as a preservative, and water forinjection, USP adjusted with acetic acid to pH 3.4-3.6.

The chemical name of vasopressin is Cyclo (1-6)L-Cysteinyl-L-Tyrosyl-L-Phenylalanyl-L-Glutaminyl-L-Asparaginyl-L-Cysteinyl-L-Prolyl-L-Arginyl-L-Glycinamide.Vasopressin is a white to off-white amorphous powder, freely soluble inwater. The structural formula of vasopressin is:

Molecular Formula: C₄₆H₆₅N₁₅O₁₂S₂; Molecular Weight: 1084.23

One mg of vasopressin is equivalent to 530 units. Alternatively, one mgof vasopressin is equivalent to 470 units.

The vasoconstrictive effects of vasopressin are mediated by vascular V1receptors. Vascular V1 receptors are directly coupled to phopholipase C,resulting in release of calcium, leading to vasoconstriction. Inaddition, vasopressin stimulates antidiuresis via stimulation of V2receptors which are coupled to adenyl cyclase.

At therapeutic doses, exogenous vasopressin elicits a vasoconstrictiveeffect in most vascular beds including the splanchnic, renal, andcutaneous circulation. In addition, vasopressin at pressor dosestriggers contractions of smooth muscles in the gastrointestinal tractmediated by muscular V1-receptors and release of prolactin and ACTH viaV3 receptors. At lower concentrations typical for the antidiuretichormone, vasopressin inhibits water diuresis via renal V2 receptors. Inpatients with vasodilatory shock, vasopressin in therapeutic dosesincreases systemic vascular resistance and mean arterial blood pressureand reduces the dose requirements for norepinephrine.

Vasopressin tends to decrease heart rate and cardiac output. The pressoreffect is proportional to the infusion rate of exogenous vasopressin.Onset of the pressor effect of vasopressin is rapid, and the peak effectoccurs within 15 minutes. After stopping the infusion, the pressoreffect fades within 20 minutes. There is no evidence for tachyphylaxisor tolerance to the pressor effect of vasopressin in patients.

At infusion rates used in vasodilatory shock (0.01-0.1 units/minute),the clearance of vasopressin is 9 to 25 mL/min/kg in patients withvasodilatory shock. The apparent half-life of vasopressin at theselevels is <10 minutes. Vasopressin is predominantly metabolized and onlyabout 6% of the dose is excreted unchanged in urine. Animal experimentssuggest that the metabolism of vasopressin is primarily by liver andkidney. Serine protease, carboxipeptidase and disulfide oxido-reductasecleave vasopressin at sites relevant for the pharmacological activity ofthe hormone. Thus, the generated metabolites are not expected to retainimportant pharmacological activity.

Carcinogenesis, Mutagenesis, Impairment of Fertility.

Vasopressin was found to be negative in the in vitro bacterialmutagenicity (Ames) test and the in vitro Chinese hamster ovary (CHO)cell chromosome aberration test. In mice, vasopressin can have an effecton function and fertilizing ability of spermatozoa.

Clinical Studies.

Increases in systolic and mean blood pressure following administrationof vasopressin were observed in seven studies in septic shock and eightstudies in post-cardiotomy vasodilatory shock.

Example 8: Effect of Temperature on Vasopressin Formulations

To test the effect of temperature on the stability of vasopressinformulation, solutions containing 20 units/mL vasopressin andchlorobutanol, adjusted to pH 3.5 with acetic acid, were prepared. OnemL of each vasopressin formulations was then filled into 3 cc vials.Each Vasopressin Formulation was stored either inverted or upright forat least three months, up to 24 months, at: (i) 5° C.; (ii) 25° C. and60% relative humidity; or (iii) 40° C. and 75% humidity, and the amountof vasopressin (U/mL) and % total impurities were measured periodically.TABLES 7-12 below display the results of the experiments at 5° C. Theresults of the experiments at 25° C. are included in TABLES 13-18. Allof the experiments were performed in triplicate. The results of theexperiments at 40° C. are included in TABLES 19-24. For each temperaturetested, three lots of the vasopressin formulation were stored for 24months (5° C. and 25° C.) and 3 months (40° C.), and measurements weretaken at regular intervals during the testing periods. “NMT” as used inthe tables denotes “not more than.”

The vasopressin and impurity amounts observed in the experimentsconducted at 5° C. are shown in TABLES 7-12 below (AVP=Vasopressin).

TABLE 7 Samples stored inverted at 5° C. Time in months Test Initial 1 23 6 9 12 18 24 AVP Assay 19.4 19.4 19.4 19.3 19.5 19.4 19.5 19.4 19.32.3% 2.0% 2.1% 2.3% 2.2% 2.3% 2.6% 2.9% 2.9%

TABLE 8 Samples stored inverted at 5° C. Acceptance Time in months TestCriteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 19.7 19.7 19.7 19.719.9 19.7 19.8 19.7 19.5 Assay U/mL Total 2.7% 2.2% 2.3% 2.4% 2.1% 2.3%2.7% 2.9% 2.9% Impurities: NMT 17.0%

TABLE 9 Samples stored inverted at 5° C. Acceptance Time in months TestCriteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 19.7 19.7 19.6 19.719.8 19.7 19.9 19.8 19.5 Assay U/mL Total 2.2% 1.9% 2.0% 2.2% 2.0% 2.1%2.4% 2.6% 2.8% Impurities: NMT 17.0%

TABLE 10 Samples stored upright at 5° C. Acceptance Time in months TestCriteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 19.4 19.5 19.4 19.419.5 19.5 19.5 19.4 19.3 Assay U/mL Total 2.3% 2.1% 2.1% 2.3% 2.1% 2.3%2.5% 2.9% 2.9% Impurities: NMT 17.0%

TABLE 11 Samples stored upright at 5° C. Acceptance Time in months TestCriteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 19.7 19.7 19.6 19.719.8 19.7 19.8 19.7 19.5 Assay U/mL Total 2.7% 2.1% 2.2% 2.2% 2.2% 2.3%2.6% 2.9% 2.8% Impurities: NMT 17.0%

TABLE 12 Samples stored upright at 5° C. Acceptance Time in months TestCriteria Initial 1 2 3 6 9 12 18 24 AVP 16.0-21.0 19.7 19.7 19.6 19.719.8 19.7 19.9 19.8 19.5 Assay U/mL Total 2.2% 1.8% 2.0% 2.2% 2.2% 2.1%2.4% 2.8% 2.7% Impurities: NMT 17.0%

The vasopressin and impurity amounts observed in the experimentsconducted at 25° C. and 60% relative humidity are shown in TABLES 13-18below.

TABLE 13 Samples stored inverted at 25° C. and 60% Relative HumidityAcceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP Assay16.0-21.0 U/mL 19.8 19.4 19.1 18.8 18.3 17.5 17.3 Total Impurities: 1.1%2.4% 3.7% 4.7% 5.9% 9.0% 13.6% NMT 17.0%

TABLE 14 Samples stored inverted at 25° C. and 60% Relative HumidityAcceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP Assay16.0-21.0 U/mL 20.1 19.7 19.3 19 18.6 17.6 17.6 Total Impurities: 1.3%2.5% 3.4% 4.6% 5.6% 9.0% 13.4% NMT 17.0%

TABLE 15 Samples stored inverted at 25° C. and 60% Relative HumidityAcceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP Assay16.0-21.0 U/mL 19.9 19.6 19.2 19 18.7 18 17.4 Total Impurities: 1.5%2.6% 3.3% 4.6% 5.9% 9.0% 12.9% NMT 17.0%

TABLE 16 Samples stored upright at 25° C. and 60% Relative HumidityAcceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP Assay16.0-21.0 U/mL 19.8 19.4 19.1 18.8 18.3 17.5 17.4 Total Impurities: 1.1%2.4% 3.2% 4.8% 5.6% 9.2% 13.1% NMT 17.0%

TABLE 17 Samples stored upright at 25° C. and 60% Relative HumidityAcceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP Assay16.0-21.0 U/mL 20.1 19.7 19.4 18.9 18.6 17.8 17.7 Total Impurities: 1.3%2.5% 3.3% 4.5% 5.7% 9.1% 13.3% NMT 17.0%

TABLE 18 Samples stored upright at 25° C. and 60% Relative HumidityAcceptance Time in months Test Criteria Initial 3 6 9 12 18 24 AVP Assay16.0-21.0 U/mL 19.9 19.6 19.2 19 18.5 18.1 17.4 Total Impurities: 1.5%2.5% 3.7% 4.7% 5.9% 9.1% 13.3% NMT 17.0%

The vasopressin and impurity amounts observed in the experimentsconducted at 40° C. and 75% relative humidity are shown in TABLES 19-24below.

TABLE 19 Samples stored inverted at 40° C. Acceptance Time in monthsTest Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 19.1 18.617.3 Assay Total Impurities: 1.1% 3.7% 7.3% 10.6% NMT 17.0%

TABLE 20 Samples stored Upright at 40° C. Acceptance Time in months TestCriteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 18.9 18.5 17.2Assay Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0%

TABLE 21 Samples stored inverted at 40° C. Acceptance Time in monthsTest Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 19.3 18.717.6 Assay Total Impurities: 1.3% 3.6% 7.3% 10.3% NMT 17.0%

TABLE 22 Samples stored Upright at 40° C. Acceptance Time in months TestCriteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 18.9 18.7 17.4Assay Total Impurities: 1.3% 3.5% 7.1% 10.2% NMT 17.0%

TABLE 23 Samples stored inverted at 40° C. Acceptance Time in monthsTest Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.317.4 Assay Total Impurities: 1.5% 3.7% 6.3% 10.3% NMT 17.0%

TABLE 24 Samples stored Upright at 40° C. Acceptance Time in months TestCriteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.5Assay Total Impurities: 1.5% 3.8% 6.3% 10.5% NMT 17.0%

The results of the above experiments suggested that storage in either anupright or inverted position did not markedly affect the stability ofvasopressin. The samples held at 5° C. exhibited little fluctuation invasopressin amounts over 24 months, and the amount of total impuritiesdid not increase above 3% during the testing period (TABLES 7-12). Thesamples held at 25° C. and 60% relative humidity exhibited a decrease invasopressin amount of about 10-12% after 24 months (TABLES 13-18). Theamount of impurities observed in the samples stored at 25° C. and 60%relative humidity after 24 months exceeded 13% in some samples, whereasthe amount of impurities observed in the samples stored at 5° C. did notexceed 3% after 24 months. After about three months, the samples held at40° C. exhibited a decrease in the amount of vasopressin of about10-12%. The amount of impurities observed at 40° C. exceeded 10% afterthree months, whereas the amount of impurities observed in the samplesstored at 5° C. was less than 3% after three months (TABLES 19-24).

Experiments were also conducted on the same samples above over thecourse of the experiments to measure the amount of individual impuritiesin the samples, pH of the samples, chlorobutanol content, particulatematter, antimicrobial effectiveness, and bacterial endotoxin levels(TABLES 25-42). (NR=no reading; ND=not determined; UI=unidentifiedimpurity).

The anti-microbial effectiveness of the solution was established todetermine the amount of antimicrobial agents in the formulation thatprotect against bacterial contamination. The bullets in the tables belowindicate that the sample was not tested for anti-microbial effectivenessat that specific time point.

The bacterial endotoxin levels were also measured for some of theformulations. The bullets in the tables below indicate that the samplewas not tested for bacterial endotoxin levels at that specific timepoint.

TABLE 25 Samples stored inverted at 5° C. Acceptance Time in months TestCritoia Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.4 19.4 19.419.3 19.5 19.4 19.5 19.4 19.3 Assay U/mL Related SEQ ID 0.5% 0.5% 0.6%0.6% 0.6% 0.6% 0.7% 0.8% 0.9% Substances NO.: 2 NMT 6.0% SEQ ID 0.6%0.6% 0.6% 0.7% 0.7% 0.7% 0.8% 0.9% 1.0% NO.: 4: NMT 6.0% SEQ ID 0.3%0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1%0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP- NR NR NR NR NR NRNR NR NR Dimer: NMT 1.0% Acetyl- 0.3% 0.2% 0.3% 0.3% 0.2% 0.2% 0.3% 0.3%0.3% AVP: NMT 1.0% UI-0.84: NR NR 0.1% NR NR NR NR NR NR NMT 1.0%UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67%NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NRNR NMT 1.0% UI-2.05: 0.1% NR 0.1% NR NR NR NR NR NR NMT 1.0% Total 2.3%2.0% 2.1% 2.3% 2.2% 2.3% 2.6% 2.9% 2.9% Impurities: NMT 17.0% pH 2.5-4.53.5 3.5 3.5 3.5 3.5 3.5 3.5 3.8 3.5 Chlorobutanol 0.25-0.60 0.48% 0.49%0.48% 0.48% 0.47% 0.48% 0.48% 0.49% 0.49% % w/v Particulate NMT 6000 0 11 1 2 16 2 4 1 Matter (USP) (≥10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≥25 μm)Anti- Meets Test . . . . . . . . . Microbial Effectiveness Bacterial NMT29 . . . . . . . . . Endotoxin EU/mL

TABLE 26 Samples stored inverted at 5° C. Acceptance Time in months TestCriteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.719.7 19.9 19.7 19.8 19.7 19.5 Assay U/mL Related SEQ ID 0.6% 0.5% 0.5%0.6% 0.5% 0.6% 0.7% 0.8% 0.8% Substances NO.: 2: NMT 6.0% SEQ ID 0.6%0.6% 0.6% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% NO.: 4: NMT 6.0% SEQ ID 0.3%0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1%0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer NR NR NR NRNR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3%0.3% AVP: NMT 1.0% UI-0.75- 0.2% 0.2% 0.2% 0.2% NR 0.1% 0.2% 0.2% 0.2%0.78: NMT 1.0% UI-0.83- 0.1% 0.1% 0.1% NR 0.1% NR NR NR NR 0.84: NMT1.0% UI-1.02- 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 1.03: NMT1.0% UI-1.67: NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NRNR NR NR NR NR NR NMT 1.0% UI-2.05: 0.2% NR NR NR NR NR NR NR NR NMT1.0% Total 2.7% 2.2% 2.3% 2.4% 2.1% 2.3% 2.7% 2.9% 2.9% Impurities: NMT17.0% pH 2.5-4.5 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 Chlorobutanol0.25-0.60 0.48% 0.48% 0.48% 0.47% 0.48% 0.48% 0.49% 0.48% 0.49% % w/vParticulate NMT 6000 1 1 1 1 1 15 2 3 2 Matter (USP) (≥10 μm) NMT 600 00 0 0 0 0 0 0 0 (≥25 μm) Anti- Meets Test . . . . . . . . . MicrobialEffectiveness Bacterial NMT 29 . . . . . . . . . Endotoxin EU/mL

TABLE 27 Samples stored inverted at 5° C. Acceptance Time in months TestCriteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.619.7 19.8 19.7 19.9 19.8 19.5 Assay U/mL Related SEQ ID 0.5% 0.5% 0.5%0.5% 0.5% 0.6% 0.6% 0.8% 0.8% Substances NO.: 2: NMT 6.0% SEQ ID 0.5%0.5% 0.5% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% NO.: 4: NMT 6.0% SEQ ID 0.3%0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1%0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NRNR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3%0.3% AVP: NMT 1.0% UI-0.75- NR NR NR NR NR NR NR NR NR 0.78: NMT 1.0%UI-0.83- NR NR 0.1% NR NR NR NR NR 0.1% 0.84: NMT 1.0% UI-1.02- 0.2%0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% 1.03: NMT 1.0% UI-1.67: NR NR NRNR NR NR NR NR 0.2% NMT 1.0% UI-1.76: NR NR NR 0.1% NR NR NR NR NR NMT1.0% UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR NRNR NR NR NR NR NR NMT 1.0% Total 2.2% 1.9% 2.0% 2.2% 2.0% 2.1% 2.4% 2.6%2.8% Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.5 3.6 3.5 3.5 3.5 3.6 3.53.5 Chlorobutano. 0.25-0.60 0.47% 0.48% 0.47% 0.47% 0.47% 0.47% 0.48%0.48% 0.48% % w/v Particulate NMT 6000 1 2 1 2 1 4 2 1 3 Matter (USP)(≥10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≥25 μm) Anti- Meets Test . . . . . .. . . Microbial Effectiveness Bacterial NMT 29 . . . . . . . . .Endotoxin EU/mL

TABLE 28 Samples stored upright at 5° C. Acceptance Time in months TestCriteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.4 19.5 19.419.4 19.5 19.5 19.5 19.4 19.3 Assay U/mL Related SEQ ID 0.5% 0.6% 0.6%0.6% 0.6% 0.6% 0.7% 0.8% 0.9% Substances NO.: 2: NMT 6.0% SEQ ID 0.6%0.6% 0.6% 0.7% 0.7% 0.7% 0.7% 0.9% 1.0% NO.: 4: NMT 6.0% SEQ ID 0.3%0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1%0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP- NR NR NR NR NR NRNR NR NR Dimer: NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.2% 0.2% 0.3% 0.3% 0.3%0.3% AVP: NMT 1.0% UI-0.84: NR NR 0.1% NR NR NR NR NR NR NMT 1.0%UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% NMT 1.0% UI-1.67:NR NR NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NR NR NR NR NRNR NMT 1.0% UI-2.05: 0.1% NR NR NR NR NR NR NR NR NMT 1.0% Total 2.3%2.1% 2.1% 2.3% 2.1% 2.3% 2.5% 2.9% 2.9% Impurities: NMT 17.0% pH 2.5-4.53.5 3.5 3.5 3.5 3.5 3.5 3.5 3.8 3.5 Chlorobutanol 0.25-0.60% 0.48% 0.48%0.48% 0.48% 0.48% 0.48% 0.48% 0.49% 0.49% w/v Particulate NMT 6000 0 2 22 1 2 2 4 1 Matter (USP) (≥10 μm) NMT 600 0 0 0 0 0 0 0 0 0 (≥25 μM)Anti- Meets Test • • • • • • • • • Microbial Effectiveness Bacterial NMT29 • • • • • • • • • Endotoxin EU/mL

TABLE 29 Samples stored upright at 5° C. Acceptance Time in months TestCriteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.619.7 19.8 19.7 19.8 19.7 19.5 Assay U/mL Related SEQ ID 0.6% 0.5% 0.5%0.5% 0.6% 0.6% 0.6% 0.8% 0.7% Substances NO.: 2: NMT 6.0% SEQ ID 0.6%0.6% 0.6% 0.6% 0.6% 0.7% 0.7% 0.8% 0.8% NO.: 4: NMT 6.0% SEQ ID 0.3%0.3% 0.3% 0.3% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1%0.1% 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NRNR NR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.2% 0.3% 0.3% 0.3%0.3% AVP: NMT 1.0% UI-0.75- 0.2% 0.2% NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2%0.78: NMT 1.0% UI-0.83- 0.1% NR 0.1% NR NR NR NR NR NR 0.84: NMT 1.0%UI-1.02- 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.3% 0.3% 0.2% 1.03: NMT 1.0%UI-1.67: NR NR NR 0.2% NR NR NR NR 0.2% NMT 1.0% UI-1.85: 0.2% NR NR NRNR NR NR NR NR NMT 1.0% UI-2.05: 0.2% NR NR NR NR NR NR NR NR NMT 1.0%Total 2.7% 2.1% 2.2% 2.2% 2.2% 2.3% 2.6% 2.9% 2.8% Impuritites: NMT17.0% pH 2.5-4.5 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6 Chlorobutanol0.25-0.60% 0.48% 0.48% 0.48% 0.48% 0.48% 0.48% 0.49% 0.49% 0.49% w/vParticulate NMT 6000 1 1 1 2 2 6 4 4 1 Matter (USP) (≥10 μm) NMT 600 0 00 0 0 0 0 0 0 (≥25 μm) Anti- Meets Test • • • • • • • • • MicrobialEffectiveness Bacterial NMT 29 • • • • • • • • • Endotoxin EU/mL

TABLE 30 Samples stored upright at 5° C. Acceptance Time in months TestCriteria Initial 1 2 3 6 9 12 18 24 Vasopressin 16.0-21.0 19.7 19.7 19.619.7 19.8 19.7 19.9 19.8 19.5 Assay U/mL Related SEQ ID 0.5% 0.5% 0.5%0.5% 0.5% 0.6% 0.6% 0.8% 0.8% Substances NO.: 2: NMT 6.0% SEQ ID 0.5%0.5% 0.5% 0.6% 0.6% 0.7% 0.7% 0.8% 0.9% NO.: 4: NMT 6.0% SEQ ID 0.3%0.3% 0.3% 0.4% 0.3% 0.3% 0.4% 0.4% 0.3% NO.: 10: NMT 1.0% Asp5-AVP: 0.1%NR 0.1% 0.1% 0.1% 0.1% 0.2% 0.2% 0.2% NMT 1.5% AVP-Dimer: NR NR NR NR NRNR NR NR NR NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.2% 0.3% 0.3% 0.3%0.3% AVP: NMT 1.0% UI-0.75- NR NR NR NR 0.2% NR NR NR NR 0.78: NMT 1.0%UI-0.83- NR NR 0.1% NR NR NR NR 0.1% NR 0.84: NMT 1.0% UI-1.02- 0.2% 0.20.2% 0.3% 0.2% 0.2% 0.3% 0.3% 0.2% 1.03: NMT 1.0% UI-1.67: NR NR NR NRNR NR NR NR 0.2% NMT 1.0% UI-1.76: NR NR NR 0.1% NR NR NR NR NR NMT 1.0%UI-1.85: 0.2% NR NR NR NR NR NR NR NR NMT 1.0% UI-2.05: 0.1% NR NR NR NRNR NR NR NR NMT 1.0% Total 2.2% 1.8% 2.0% 2.2% 2.2% 2.1% 2.4% 2.8% 2.7%Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.5 3.6 3.5 3.5 3.5 3.6 3.5 3.5Chlorobutanol 0.25-0.60% 0.47% 0.48% 0.47% 0.47% 0.48% 0.47% 0.48% 0.48%0.48% w/v Particulate NMT 6000 1 1 1 1 1 3 2 1 3 Matter (USP) (≥10 μm)NMT 600 0 0 0 0 0 0 0 0 0 (≥25 μm) Anti- Meets Test • • • • • • • • •Microbial Effectiveness Bacterial NMT 29 • • • • • • • • • EndotoxinEU/mL

TABLE 31 Samples stored inverted at 25° C. and 60% Relative HumidityAcceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30Vasopressin 16.0-21.0 19.8 19.4 19.1 18.8 18.3 17.5 17.3 — Assay U/mLRelated SEQ ID 0.1% 0.5% 1.1% 1.6% 2.0% 3.3% 4.6% — Substances NO.: 2:NMT 6.0% SEQ ID 0.1% 0.6% 1.2% 1.8% 2.2% 3.7% 5.2% — NO.: 4: NMT 6.0%SEQ ID 0.3% 0.4% 0.5% 0.5% 0.4% 0.2% 0.3% — NO.: 10: NMT 1.0% Asp5-AVP:NR 0.1% 0.3% 0.4% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NRNR — NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — AVP: NMT 1.0%UI-0.83: NR NR <0.10 NR NR NR 0.1% — NMT 1.0% UI-0.99: NR NR NR NR 0.1%NR NR — NMT 1.0% UI-1.03: 0.2% 0.2% 0.3% 0.3% 0.3% 0.2% 0.2% — NMT 1.0%UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1%0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NRNR NR NR NR NR 0.1% — NMT 1.0% UI-1.56- NR NR <0.10 0.1% 0.1% 0.2% 0.2%— 1.57: NMT 1.0% UI-1.60: NR NR NR 0.1% 0.1% 0.2% NR — NMT 1.0% UI-1.74:NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85- NR 0.2% NR NR NR 0.1% 0.1% —1.88: NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR NR 0.4% — NMT 1.0%UI-2.15-2.16: NR NR 0.1% NR NR NR 0.5% — NMT 1.0% Total 1.1% 2.4% 3.7%4.7% 5.9% 9.0% 13.6% — Impurities: NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.53.4 3.3 3.2 — Chlorobutanol 0.25-0.60% 0.49% 0.48% 0.48% 0.47% 0.47%0.48% 0.47% — w/v Particulate NMT 6000 1 1 1 1 8 4 1 — Matter (USP) (≥10μm) NMT 600 0 0 0 0 0 0 0 — (≥25 μm) AntiMicrobial Meets Test Pass • • •Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 —Endotoxin EU/mL

TABLE 32 Samples stored inverted at 25° C. and 60% Relative HumidityAcceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30Vasopressin 16.0-21.0 20.1 19.7 19.3 19 18.6 17.6 17.6 — Assay U/mLRelated SEQ ID NO.: 0.1% 0.5% 0.9% 1.5% 1.9% 3.1% 4.4% — Substances 2:NMT 6.0% SEQ ID NO.: 0.1% 0.5% 1.1% 1.6% 2.2% 3.4% 4.9% — 4: NMT 6.0%SEQ ID NO.: 0.3% 0.4% 0.3% 0.4% 0.3% 0.4% 0.3% — 10: NMT 1.0% Asp5-AVP:NR 0.1% 0.2% 0.3% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NRNR — NMT 1.0% Acetyl-AVP 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — NMT 1.0%UI-0.75-0.76: NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% — NMT 1.0% UI-0.83: 0.2%NR 0.1% NR NR 0.1% 0.1% — NMT 1.0% UI-099: NR NR NR NR 0.1% NR NR — NMT1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.3% 0.2% — NMT 1.0%UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1%0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NRNR NR NR NR NR 0.1% — NMT 1.0% UI-1.56-1.57: NR NR 0.1% 0.1% 0.2% 0.2%0.2% — NMT 1.0% UI-1.60: NR NR 0.1% 0.1% 0.2% 0.2% NR — NMT 1.0%UI-1.74: NR NR NR NR NR 0.2% NR — NMT 1.0% UI-1.85-1.88: NR 0.2% NR NRNR 0.1% 0.1% — NMT 1.0% UI-2.09-2.10: NR 0.2% NR NR NR NR 0.4% — NMT1.0% UI-2.15-2.16: NR NR NR NR NR NR 0.6% — NMT 1.0% Total 1.3% 2.5%3.4% 4.6% 5.6% 9.0% 13.4% — Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.6 3.53.5 3.2 3.3 3.4 — Chlorobutanol 0.25-0.60% 0.48% 0.49% 0.48% 0.47% 0.47%0.47% 0.47% — w/v Particulate NMT 6000 2 1 1 3 4 1 2 — Matter (≥10 μm)(USP) NMT 600 0 0 0 0 0 0 0 — (≥25 μm) AntiMicrobial Meets Test Pass • •• Pass • Pass — Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 —Endotoxin EU/mL

TABLE 33 Samples stored inverted at 25° C. and 60% Relative HumidityAcceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30Vasopressin 16.0- 21.0 19.9 19.6 19.2 19 18.7 18 17.4 — Assay U/mLRelated SEQ ID NO.: 0.2% 0.5% 1.0% 1.5% 2.0% 3.2% 4.5% — Substances 2:NMT 6.0% SEQ ID NO.: 0.1% 0.6% 1.1% 1.8% 2.2% 3.7% 5.0% — 4: NMT 6.0%SEQ ID NO.: 0.4% 0.4% 0.3% 0.4% 0.4% 0.3% 0.5% — 10: NMT 1.0% Asp5-AVP:NR 0.1% 0.2% 0.4% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR0.1% — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% — NMT1.0% UI-0.12: NR 0.1% NR NR NR NR NR NMT 1.0% UI-0.75-0.76: NR NR NR NRNR NR NR NMT 1.0% UI-0.83-0.84: NR 0.1% 0.1% 0.1% 0.1% 0.1% NMT 1.0%UI-0.93: NR NR NR NR NR NR 0.1% NMT 1.0% UI-0.99: NR NR NR NR NR NR NRNMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% — NMT 1.0%UI-1.15: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1%0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR NR NMT 1.0% UI-1.22: NR NR NRNR NR NR 0.1% NMT 1.0% UI-1.26: NR NR NR NR NR NR NMT 1.0% UI-1.35: 0.3%NR NR NR NR NR NR NMT 1.0% UI-1.56-1.57: NR NR 0.1% NR 0.1% 0.2% 0.3%NMT 1.0% UI-1.60: NR NR 0.1% NR 0.1% NR NR — NMT 1.0% UI-1.74: NR NR NRNR NR NR NR NMT 1.0% UI-1.84-1.89: NR 0.1% NR NR NR NR 0.2% NMT 1.0%UI-1.96: 0.2% NR NR NR NR NR NR NMT 1.0% UI-2.09-2.10: NR 20.0% NR NR NR<0.10 0.1% NMT 1.0% UI-2.15-2.16: NR NR 0.1% NR NR 0.1% NR NMT 1.0%Total 1.5% 2.6% 3.3% 4.6% 5.9% 9.0% 12.9% — Impurities: NMT 17.0% pH2.5-4.5 3.6 3.5 3.5 3.5 3.4 3.4 3.3 — Chlorobutanol 0.25-0.60% 0.48%0.47% 0.47% 0.46% 0.46% 0.46% 0.45% — w/v Particulate NMT 6000 1 2 3 3 31 2 — Matter (≥10 μm) (USP) NMT 600 0 0 0 0 0 0 0 — (≥25 μm) Anti- MeetsTest Pass • • • Pass • Pass — Microbial Effectiveness Bacterial NMT 29<1 • • • <1 • <1 — Endotoxin EU/mL

TABLE 34 Samples stored upright at 25° C. and 60% Relative HumidityAcceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30Vasopressin 16.0-21.0 19.8 19.4 19.1 18.8 18.3 17.5 17.4 — Assay U/mLRelated SEQ ID NO.: 0.1% 0.5% 1.1% 1.6% 2.0% 3.2% 4.5% — Substances 2:NMT 6.0% SEQ ID NO.: 0.1% 0.6% 1.2% 1.8% 2.3% 3.6% 5.0% — 4: NMT 6.0%SEQ ID NO.: 0.3% 0.4% 0.3% 0.4% 0.3% 0.2% 0.3% — 10: NMT 1.0% Asp5-AVP:NR 0.1% 0.2% 0.4% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NRNR — NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% 0.2% 0.2% 0.3% — NMT 1.0%UI-0.83: NR NR <0.10 NR NR 0.1% 0.1% — NMT 1.0% UI-0.99: NR NR NR NR NRNR NR — NMT 1.0% UI-1.03: 0.2% 0.2% 0.2% 0.3% 0.2% 0.2% 0.2% — NMT 1.0%UI-1.14: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.18: NR NR NR NR NR 0.1%0.3% — NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% — NMT 1.0% UI-1.22: NRNR NR NR NR NR NR — NMT 1.0% UI-1.56-1.57: NR NR NR 0.1% 0.1% 0.2% 0.2%— NMT 1.0% UI-1.60: NR NR NR NR NR 0.1% NR — NMT 1.0% UI-1.74: NR NR NRNR NR 0.2% NR — NMT 1.0% UI-1.85-1.88: NR 0.2% NR NR NR 0.1% 0.1% — NMT1.0% UI-2.09-2.10: NR 0.2% NR NR NR NR 0.3% — NMT 1.0% UI-2.15-2.16: NRNR NR NR NR NR 0.5% — NMT 1.0% Total 1.1% 2.4% 3.2% 4.8% 5.6% 9.2% 13.1%— Impurities: NMT 17.0% pH 2.5-4.5 3.5 3.5 3.5 3.5 3.4 3.3 3.3 —Chlorobutanol 0.25-0.60% 0.49% 0.48% 0.48% 0.48% 0.47% 0.48% 0.47% — w/vParticulate NMT 6000 1 2 2 2 2 4 2 — Matter (≥10 μm) (USP) NMT 600 0 0 00 0 0 0 — (≥25 μm) AntiMicrobial Meets Test Pass • • • Pass • Pass —Effectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL

TABLE 35 Samples stored upright at 25° C. and 60% Relative HumidityAcceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30Vasopressin 16.0-21.0 20.1 19.7 19.4 18.9 18.6 17.8 17.7 — Assay U/mLRelated SEQ ID 0.1% 0.5% 0.9% 1.4% 1.9% 3.1% 4.3% — Substances NO.: 2:NMT 6.0% SEQ ID 0.1% 0.5% 1.1% 1.6% 2.2% 3.4% 4.9% — NO.: 4: NMT 6.0%D-Asn- 0.3% 0.4% 0.3% 0.3% 0.3% 0.4% 0.3% — AVP: NMT 1.0% Asp5-AVP: NR0.1% 0.2% 0.3% 0.4% 0.7% 0.9% — NMT 1.5% AVP-Dimer: NR NR NR NR NR NR NR— NMT 1.0% Acetyl- 0.30% 0.30% 0.30% 0.20% 0.20% 0.20% 0.3% — AVP: NMT1.0% UI-0.75- NR 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.76: NMT 1.0% UI-0.83%0.2% NR <0.10 NR NR 0.1% 0.1% NMT 1.0% UI-0.99: NR NR NR NR 0.1% NR NRNMT 1.0% UI-1.02- 0.2% 0.2% 0.2% 0.2% 0.2% 0.3% 0.2% — 1.03: NMT 1.0%UI-1.14 NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1%0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.22: NR NR NRNR NR NR 0.4% NMT 1.0% UI-1.56- NR NR 0.1% 0.1% 0.2% 0.2% 0.3% 1.57: NMT1.0% UI-1.60: NR NR 0.1% 0.1% 0.2% 0.2% NR — NMT 1.0% UI-1.74: NR NR NRNR NR 0.2% NR NMT 1.0% UI-1.85- NR 0.2% NR NR NR 0.1% 0.1 1.88: NMT 1.0%UI-2.09- NR 0.2% NR NR NR 0.1% 0.3 2.10: NMT 1.0% UI-2.15- NR NR NR NRNR 0.5 2.16: NMT 1.0% Total 1.3% 2.5% 3.3% 4.5% 5.7% 9.1% 13.3 —Impurities: NMT 17.0% pH 2.5-4.5 3.6 3.6 3.5 3.5 3.4 3.3 3.3 —Chlorobutanol 0.25-0.60% 0.48% 0.49% 0.48% 0.47% 0.47% 0.48% 0.46% — w/vParticulate NMT 6000 2 1 1 2 5 1 4 — Matter (USP) (≥10 μm) NMT 600 0 0 00 0 0 0 — (≥25 μm) Anti- Meets Test Pass • • • Pass • Pass — MicrobialEffectiveness Bacterial NMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL

TABLE 36 Samples stored upright at 25° C. and 60% Relative HumidityAcceptance Time in months Test Criteria Initial 3 6 9 12 18 24 30Vasopressin 16.0-21.0 19.9 19.6 19.2 19 18.5 18.1 17.4 — Assay U/mLRelated SEQ ID 0.2% 0.5% 1.0% 1.5% 2.1% 3.3% 4.7% — Substances NO.: 2:NMT 6.0% SEQ ID 0.1% 0.6% 1.1% 1.7% 2.3% 3.7% 5.3% — NO.: 4: NMT 6.0%D-Asn- 0.4% 0.4% 0.3% 0.4% 0.4% 0.3% 0.5% — AVP: NMT 1.0% Asp5-AVP: NR0.1% 0.2% 0.3% 0.5% 0.7% 1.0% — NMT 1.5% AVP-Dimer NR NR NR NR NR NR NR— NMT 1.0% Acetyl- 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% 0.3% — AVP: NMT 1.0%UI-0.12: NR NR NR NR NR NR NR NMT 1.0% UI-0.75- NR NR NR NR NR NR NR0.76: NMT 1.0% UI-0.83- NR 0.1% 0.1% 0.1% NR 0.1% 0.1% 0.84: NMT 1.0%UI-0.93: NR NR NR NR NR NR 0.1% NMT 1.0% UI-0.99: NR NR NR NR NR NR NRNMT 1.0% UI-1.02- 0.3% 0.2% 0.2% 0.3% 0.3% 0.3% 0.3% — 1.03: NMT 1.0%UI-1.15: NR NR NR NR NR NR 0.2% NMT 1.0% UI-1.18: NR NR NR NR NR 0.1%0.3% NMT 1.0% UI-1.20: NR NR NR NR NR NR 0.1% NMT 1.0% UI-1.22: NR NR NRNR NR NR NR NMT 1.0% UI-1.26: NR NR 0.4% NR NR NR NR NMT 1.0% UI-1.35:0.1% NR NR NR NR NR NR NMT 1.0% UI-1.56- NR NR 0.1% 0.1% NR 0.2% 0.3%1.57: NMT 1.0% UI-1.60: NR NR NR NR NR NR NR — NMT 1.0% UI-1.74: NR NRNR NR NR NR NR — NMT 1.0% UI-1.84- NR 0.1% NR NR NR NR 0.2% 1.89: NMT1.0% UI-1.96: 0.2% NR NR NR NR NR NR NMT 1.0% UI-2.09- NR NR NR NR NR<0.10 NR 2.10: NMT 1.0% UI-2.15- NR NR 0.1% NR NR 0.2% NR 2.16: NMT 1.0%Total 1.5% 2.5% 3.7% 4.7% 5.9% 9.1% 13.3% Impurities: NMT 17.0% pH2.5-4.5 3.6 3.5 3.5 3.5 3.4 3.4 3.3 — Chlorobutanol 0.25-0.60 0.48% 0.48%  0.47%  0.47%  0.46%  0.45 0.46 — % w/v Particulate NMT 6000 1 0 13 7 0 3 — Matter (USP) (≥10 μm) NMT 600 0 0 0 0 0 0 0 — (≥25 μm) Anti-Meets Test Pass • • • Pass • Pass — Microbial Effectiveness BacterialNMT 29 <1 • • • <1 • <1 — Endotoxin EU/mL

TABLE 37 Samples stored inverted at 40° C. Acceptance Time in monthsTest Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 19.1 18.617.3 Assay Related SEQ ID NO.: 2: 0.1% 1.0% 2.4% 3.8% Substances NMT6.0% SEQ ID NO.: 4: 0.1% 1.1% 2.7% 4.3% NMT 6.0% D-Asn-AVP: 0.3% 0.4%0.3% 0.3% NMT 1.0% Asp5-AVP: ND 0.2% 0.5% 0.8% NMT 1.5% AVP-Dimer: ND NDND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.2% 0.2% NMT 1.0% UI-0.13: NMT ND0.1% ND ND 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.83-0.84: ND NDND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: NMTND ND ND 0.2% 1.0% UI-1.56-1.57: ND 0.2% 0.4% 0.4% NMT 1.0% UI-1.67: NMTND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.83-1.85: ND ND 0.2%0.2% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: NMT ND0.1% ND ND 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% Total Impurities:1.1% 3.7% 7.3% 10.6% NMT 17.0% pH 2.5-4.5 3.5 3.3 3.2 3.1 Chlorobutanol0.25-0.60% w/v 0.49% 0.48% 0.50% 0.47% Particulate NMT 6000 (≥10 1 1 1 1Matter (USP) μm) NMT 600 (≥25 0 0 0 0 μm)

TABLE 38 Samples stored inverted at 40° C. Acceptance Time in monthsTest Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 19.3 18.717.6 Assay Related SEQ ID NO.: 2: 0.1% 0.9% 2.2% 3.6% Substances NMT6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.5% 3.9% NMT 6.0% D-Asn-AVP: 0.3% 0.4%0.3% 0.3% NMT 1.0% Asp5-AVP: ND 0.2% 0.5% 0.8% NMT 1.5% AVP-Dimer: ND NDND ND NMT 1.0% Acetyl-AVP: 0.3% 0.2% 0.3% 0.2% NMT 1.0% UI-0.13: NMT ND0.1% ND ND 1.0% UI-0.75-0.78: ND ND 0.2% 0.2% NMT 1.0% UI-0.80-0.84:0.2% 0.2% ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.3% 0.2% 0.3% NMT 1.0%UI-1.18: NMT ND ND 0.3% 0.2% 1.0% UI-1.56-1.57: ND 0.2% ND 0.4% NMT 1.0%UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0%UI-1.81-1.85: ND ND 0.2% 0.2% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT1.0% UI-1.93: NMT ND 0.1% ND ND 1.0% UI-2.03-2.08: ND ND 0.2% 0.1% NMT1.0% UI-2.14: NMT ND ND 0.2% ND 1.0% Total Impurities: 1.3% 3.6% 7.3%10.3% NMT 17.0% pH 2.5-4.5 3.6 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v0.48% 0.48% 0.50% 0.47% Particulate NMT 6000 (≥10 2 2 1 1 Matter (USP)μm) NMT 600 (≥25 0 0 0 0 μm)

TABLE 39 Samples stored inverted at 40° C. Acceptance Time in monthsTest Criteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.317.4 Assay Related SEQ ID NO.: 2: 0.2% 0.9% 2.2% 3.8% Substances NMT6.0% SEQ ID NO.: 4: 0.1% 1.0% 2.4% 4.0% NMT 6.0% D-Asn-AVP: 0.4% 0.3%0.3% 0.3% NMT 1.0% Asp5-AVP: ND 0.2% 0.5% 0.8% NMT 1.5% AVP-Dimer: ND NDND ND NMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% NMT 1.0% UI-0.13: NMT NDND ND ND 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.80-0.84: ND ND NDND NMT 1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% NMT 1.0% UI-1.18: NMT NDND ND 0.2% 1.0% UI-1.35: NMT 0.1% ND ND ND 1.0% UI-1.52-1.58: ND 0.2%0.3% 0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND NDND 1.0% UI-1.81-1.85: ND ND ND ND NMT 1.0% UI-1.86-1.88: ND 0.1% 0.2% NDNMT 1.0% UI-1.91-1.96: 0.2% 0.2% ND ND NMT 1.0% UI-2.02-2.08: ND ND ND0.2% NMT 1.0% UI-2.11-2.14: ND 0.2% ND ND NMT 1.0% Total Impurities:1.5% 3.7% 6.3% 10.3% NMT 17.0% pH 2.5-4.5 3.6 3.4 3.2 3.1 Chlorobutanol0.25-0.60% w/v 0.48% 0.47% 0.46% 0.46% Particulate NMT 6000 (≥10 2 2 1 1Matter (USP) μm) NMT 600 (≥25 0 0 0 0 μm)

TABLE 40 Samples stored Upright at 40° C. Acceptance Time in months TestCriteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.8 18.9 18.5 17.2Assay Related SEQ ID NO.: 2: 0.1% 1.0% 2.4% 3.8% Substances NMT 6.0% SEQID NO.: 4: 0.1% 1.1% 2.7% 4.3% NMT 6.0% D-Asn-AVP: 0.3% 0.3% 0.3% 0.3%NMT 1.0% Asp5-AVP: ND 0.2% 0.5% 0.8% NMT 1.5% AVP-Dimer: ND ND ND ND NMT1.0% UI-0.13: NMT ND 0.1% ND ND 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0%UI-0.83-0.84: ND ND ND ND NMT 1.0% UI-1.02-1.03: 0.2% 0.2% 0.2% 0.2% NMT1.0% UI-1.18: NMT ND ND ND 0.2% 1.0% UI-1.56-1.57: ND 0.2% 0.3% 0.3% NMT1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0%UI-1.83-1.85: ND ND 0.2% ND NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT1.0% UI-1.93: NMT ND 0.1% ND ND 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT1.0% Total Impurities: 1.1% 3.6% 7.2% 10.3% NMT 17.0% Total Impurities:1.1% 3.6% 7.2% 10.3% NMT 17.0% pH 2.5-4.5 3.5 3.3 3.2 3.1 Chlorobutanol0.25-0.60% w/v 0.49% 0.48% 0.50% 0.48% Particulate NMT 6000 (≥10 1 1 1 1Matter (USP) μm) NMT 600 (≥25 0 0 0 0 μm)

TABLE 41 Samples stored Upright at 40° C. Acceptance Time in months TestCriteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 20.1 18.9 18.7 17.4Assay Related SEQ ID NO.: 2: 0.1% 0.9% 2.3% 3.7% Substances NMT 6.0% SEQID NO.: 4: 0.1% 1.0% 2.5% 3.9% NMT 6.0% D-Asn-AVP: 0.3% 0.4% 0.3% 0.3%NMT 1.0% Asp5-AVP: ND 0.2% 0.5% 0.8% NMT 1.5% AVP-Dimer: ND ND ND ND NMT1.0% Acetyl-AVP: 0.3% 0.2% 0.3% 0.2% NMT 1.0% UI-0.13: NMT ND ND ND ND1.0% UI-0.75-0.78: ND ND 0.2% 0.2% NMT 1.0% UI-0.80-0.84: 0.2% 0.2% NDND NMT 1.0% UI-1.02-1.03: 2.0% 0.3% 0.2% 0.3% NMT 1.0% UI-1.18: NMT NDND ND 0.2% 1.0% UI-1.56-1.57: ND 0.2% 0.4% 0.4% NMT 1.0% UI-1.67: NMT NDND ND ND 1.0% UI-1.76: NMT ND ND ND ND 1.0% UI-1.83-1.85: ND ND 0.2%0.1% NMT 1.0% UI-1.87-1.88: ND ND 0.2% 0.2% NMT 1.0% UI-1.93: NMT ND0.1% ND ND 1.0% UI-2.05-2.08: ND ND 0.2% ND NMT 1.0% UI-2.14: NMT ND NDND ND 1.0% Total Impurities: 1.3% 3.5% 7.1% 10.2% NMT 17.0% pH 2.5-4.53.6 3.3 3.2 3.1 Chlorobutanol 0.25-0.60% w/v 0.48% 0.48% 0.49% 0.47%Particulate NMT 6000 (≥10 2 1 1 1 Matter (USP) μm) NMT 600 (≥25 0 0 0 0μm)

TABLE 42 Samples stored Upright at 40° C. Acceptance Time in months TestCriteria Initial 1 2 3 Vasopressin 18.0-21.0 U/mL 19.9 19.2 18.3 17.5Assay Related SEQ ID NO.: 2: 0.2% 1.0% 2.2% 3.9% Substances NMT 6.0% SEQID NO.: 4: 0.1% 1.1% 2.4% 4.2% NMT 6.0% D-Asn-AVP: 0.4% 0.3% 0.3% 0.3%NMT 1.0% Asp5-AVP: ND 0.2% 50.0% 0.8% NMT 1.5% AVP-Dimer: ND ND ND NDNMT 1.0% Acetyl-AVP: 0.3% 0.3% 0.3% 0.2% NMT 1.0% UI-0.13: NMT ND ND NDND 1.0% UI-0.75-0.78: ND ND ND ND NMT 1.0% UI-0.80-0.84: ND ND ND ND NMT1.0% UI-1.02-1.03: 0.3% 0.2% 0.2% 0.3% NMT 1.0% UI-1.18: NMT ND ND ND0.2% 1.0% UI-1.35: NMT 0.1% ND ND ND 1.0% UI-1.52-1.58: ND 0.2% 0.3%0.4% NMT 1.0% UI-1.67: NMT ND ND ND ND 1.0% UI-1.76: NMT ND ND ND ND1.0% UI-1.83-1.85: ND ND ND ND NMT 1.0% UI-1.86-1.88: ND 0.1% 0.2% NDNMT 1.0% UI-1.91-1.96: 0.2% 0.2% ND ND NMT 1.0% UI-2.02-2.08: ND ND ND0.1% NMT 1.0% UI-2.11-2.14: ND 0.2% ND ND NMT 1.0% Total Impurities:1.5% 3.8% 6.3% 10.5% NMT 17.0% pH 2.5-4.5 3.6 3.4 3.2 3.1 Chlorobutanol0.25-0.60% w/v 0.48% 0.47% 0.47% 0.45% Particulate NMT 6000 (≥10 1 2 1 1Matter (USP) μm) NMT 600 (≥25 0 0 0 0 μm)

Example 9: Effect of pH 3.5-4.5 on Vasopressin Formulations

To test of effect of pH on vasopressin formulations, solutionscontaining 20 units/mL vasopressin, adjusted to pH 3.5, 3.6, 3.7, 3.8,3.9, 4, 4.1, 4.2, 4.3, 4.4, or 4.5 with 10 mM acetate buffer, wereprepared. One mL of each of the vasopressin formulations was then filledinto 10 cc vials.

The vasopressin formulations were stored for four weeks at: (i) 25° C.;or (ii) 40° C., and the assay (% label claim; vasopressin remaining) and% total impurities after four weeks were measured using the methodsdescribed in EXAMPLE 1. FIGS. 11 and 12 below display the results of theexperiments at 25° C. The results of the experiments at 40° C. areincluded in FIGS. 13 and 14.

The results of the experiments suggested that the stability of avasopressin formulation was affected by pH. At 25° C., the remainingvasopressin after four weeks was highest between pH 3.6 and pH 3.8 (FIG.11). Within the range of pH 3.6 to pH 3.8, the level of impurities waslowest at pH 3.8 (FIG. 12). At 25° C., pH 3.7 provided the higheststability for vasopressin (FIG. 11).

At 40° C., the remaining vasopressin after four weeks was highestbetween pH 3.6 and pH 3.8 (FIG. 13). Within the range of pH 3.6 to pH3.8, the level of impurities was lowest at pH 3.8 (FIG. 14). At 40° C.,pH 3.6 provided the highest stability for vasopressin (FIG. 13),

Example 10: Effect of pH 2.5-4.5 of Vasopressin Formulations

To test of effect of pH on vasopressin formulations, solutionscontaining 20 units/mL vasopressin, adjusted to pH 2.5, 2.6, 2.7, 2.8,2.9, 3, 3.1, 3.2, 3.3, or 3.4 with 10 mM acetate buffer were alsoprepared. One mL of each of the vasopressin formulations was then filledinto 10 cc vials.

The amount of vasopressin, impurities, and associated integration valueswere determined using the methods describes in EXAMPLE 1. The resultsfrom the stability tests on the vasopressin formulations from pH 2.5 to3.4 were plotted against the results from the stability tests onvasopressin formulations from pH 3.5 to 4.5 as disclosed in EXAMPLE 9,and are displayed in FIGS. 15-18.

The assay (% label claim; vasopressin remaining) and % total impuritiesin the vasopressin pH 2.5 to 3.4 formulations after four weeks arereported in TABLE 43.

TABLE 43 % Total Batch Target pH Week Condition Vasopressin (% LC)Impurities 1A 2.5 0 25° C. 100.57 2.48 1B 2.6 0 25° C. 101.25 2.24 1C2.7 0 25° C. 101.29 2.26 1D 2.8 0 25° C. 101.53 2.00 1E 2.9 0 25° C.102.33 1.95 1F 3 0 25° C. 102.32 1.89 1G 3.1 0 25° C. 102.59 2.06 1H 3.20 25° C. 102.60 1.85 1I 3.3 0 25° C. 102.73 1.81 1J 3.4 0 25° C. 101.931.75 1A 2.5 0 40° C. 100.57 2.48 1B 2.6 0 40° C. 101.25 2.24 1C 2.7 040° C. 101.29 2.26 1D 2.8 0 40° C. 101.53 2.00 1E 2.9 0 40° C. 102.331.95 1F 3 0 40° C. 102.32 1.89 1G 3.1 0 40° C. 102.59 2.06 1H 3.2 0 40°C. 102.60 1.85 1I 3.3 0 40° C. 102.73 1.81 1J 3.4 0 40° C. 101.93 1.751A 2.5 4 25° C. 95.70 6.66 1B 2.6 4 25° C. 98.58 5.29 1C 2.7 4 25° C.98.94 4.26 1D 2.8 4 25° C. 99.14 3.51 1E 2.9 4 25° C. 100.08 3.41 1F 3 425° C. 100.29 2.92 1G 3.1 4 25° C. 100.78 2.55 1H 3.2 4 25° C. 100.742.16 1I 3.3 4 25° C. 100.46 2.14 1J 3.4 4 25° C. 100.25 2.03 1A 2.5 440° C. 81.89 19.41 1B 2.6 4 40° C. 90.10 15.60 1C 2.7 4 40° C. 92.1913.46 1D 2.8 4 40° C. 94.89 10.98 1E 2.9 4 40° C. 96.03 9.78 1F 3 4 40°C. 97.26 8.09 1G 3.1 4 40° C. 99.61 6.39 1H 3.2 4 40° C. 98.58 5.25 1I3.3 4 40° C. 97.81 4.41 1J 3.4 4 40° C. 97.35 3.85

The % total impurities for the pH 2.5 to 3.4 formulations and the pH 3.5to 4.5 formulations observed in the experiments conducted at 25° C. and40° C. are shown in FIGS. 15 (25° C.) and 16 (40° C.).

The vasopressin assay amount for the vasopressin pH 2.5 to 3.4formulations and the vasopressin pH 3.5 to 4.5 formulations observed inthe experiments conducted at 25° C. and 40° C. are shown in FIGS. 17(25° C.) and 18 (40° C.). The vasopressin assay is presented as a %assay decrease of vasopressin over the four-week study period, ratherthan absolute assay, because the amount of starting vasopressin variedbetween the vasopressin pH 2.5 to 3.4 formulations and the vasopressinpH 3.5 to 4.5 formulations.

The results of the above experiments suggested that the stability of avasopressin formulation was affected by pH. At 25° C., the percentdecrease in vasopressin after four weeks was lowest between pH 3.7 andpH 3.8 (FIG. 17). Within the range of pH 3.7 to pH 3.8, the level ofimpurities was lowest at pH 3.8 (FIG. 15). At 40° C., the percentdecrease in vasopressin after four weeks was lowest between pH 3.6 andpH 3.8 (FIG. 18). Within the range of pH 3.6 to pH 3.8, the level ofimpurities was lowest at pH 3.8 (FIG. 16).

Example 11: Intra-Assay and Inter-Analysis Precision of Vasopressin pHExperiments

The methods used to determine the % assay decrease and amount ofimpurities in the vasopressin solutions over time in EXAMPLE 10 had bothintra-assay and inter-analyst precision.

Intra-assay precision was demonstrated by performing single injectionsof aliquots of a vasopressin formulation (n=6; Chemist 1) from a commonlot of drug product and determining the assay and repeatability (% RSD;relative standard deviation). Inter-analyst precision was demonstratedby two different chemists testing the same lot of drug product; however,the chemists used different instruments, reagents, standardpreparations, columns, and worked in different laboratories. Theprocedure included a common pooling of 20 vials of vasopressin, whichwere assayed by the two chemists using different HPLC systems anddifferent HPLC columns. The vasopressin assay results (units/mL) andrepeatability (% RSD for n=6) were recorded and are reported in theTABLE 44 below.

TABLE 44 Precision of Vasopressin Results. Chemist 1 Chemist 2 Sample(units/mL) (units/mL) 1 19.74 19.65 2 19.76 19.66 3 19.77 19.66 4 19.7519.72 5 19.97 19.73 6 19.65 19.73 Mean 19.8  19.7  % RSD (≤2.0%) 0.5%0.2% % Difference = 0.5% (acceptance criteria: ≤3.0%)${\% \mspace{14mu} {Difference}} = {\frac{\left( {{{Chemist}\mspace{14mu} 1_{Mean}} - {{Chemist}{\mspace{11mu} \;}2_{Mean}}} \right)}{\left( {{{Chemist}\mspace{14mu} 1_{Mean}} + {{Chemist}{\mspace{11mu} \;}2_{Mean}}} \right)} \times 200}$

The intra-assay repeatability met the acceptance criteria (% RSD<2.0%)with values of 0.5% and 0.2%. The inter-analyst repeatability also metthe acceptance criteria (% difference<3.0%) with a difference of 0.5%.

Example 12: Effect of Citrate Versus Acetate Buffer on VasopressinFormulations

To test the effect of citrate and acetate buffer on vasopressinformulations, a total of twelve solutions of 20 Units/mL vasopressinwere prepared in 1 mM citrate buffer, 10 mM citrate buffer, 1 mM acetatebuffer, and 10 mM acetate buffer. All of the solutions were prepared intriplicate. Each solution was adjusted to pH 3.5 with hydrochloric acid.

The vasopressin formulations were stored at 60° C. for 7 days, and theassay (% label claim; vasopressin remaining) and % total impuritiesafter 7 days were analyzed by HPLC using the procedure and experimentalconditions described in EXAMPLE 1.

The assay (% label claim; vasopressin remaining) and % total impuritiesfor each of the Vasopressin Buffered Formulations are reported in theTABLES 45 and 46 below.

TABLE 45 Assay (% label claim; vasopressin remaining) in the vasopressinformulations after storage at 60° C. for 7 days. Sample Buffer 1 2 3Average 1 mM citrate buffer 89.5% 89.7% 90.6% 89.9% 10 mM citrate buffer84.1% 84.4% 84.5% 84.3% 1 mM acetate buffer 90.5% 91.1% 91.9% 91.2% 10mM acetate buffer 90.9% 90.9% 92.4% 91.4%

TABLE 46 % Total Impurities in the vasopressin formulations afterstorage at 60° C. for 7 days. Sample Buffer 1 2 3 Average 1 mM citratebuffer 3.4% 3.5% 2.5% 3.1% 10 mM citrate buffer 9.5% 9.0% 9.4% 9.3% 1 mMacetate buffer 3.3% 2.8% 3.2% 3.1% 10 mM acetate buffer 2.9% 2.6% 3.1%2.9%

The data indicated that the vasopressin assay in the vasopressinformulations with citrate buffer was lower than in the vasopressinformulations with acetate buffer. For example, at 10 mM of eithercitrate or acetate buffer, the average vasopressin assay was 91.4% inacetate buffer, but was 84.3% in citrate buffer. The data also indicatedthat % total impurities in the vasopressin formulations with citratebuffer were higher than in the vasopressin formulations with acetatebuffer. For example, at 10 mM of either citrate or acetate buffer, theaverage % total impurities was 2.9% in acetate buffer, but was 9.3% incitrate buffer.

Further, as the citrate buffer concentration increased, the vasopressinassay further decreased (from an average of 89.9% to 84.3%), and the %total impurities increased (from an average of 3.1% to 9.3%). Thiseffect was not observed in the vasopressin formulations with acetatebuffer, where the average and % total impurities stayed fairly constant.

Example 13: Multi-Dose Vasopressin Formulation

A multi-dose formulation (10 mL) for vasopressin that can be used in theclinic is detailed in TABLE 47 below:

TABLE 47 Drug Product Description Vasopressin, USP Active Ingredient 20Units (~0.04 mg) Dosage Form Injection — Route of Intravenous —Administration Description Clear colorless to practically colorlesssolution supplied in a 10 mL clear glass vial with flip-off cap

The composition of a 10 mL formulation of vasopressin is provided below.

TABLE 48 Drug Product Composition Batch Unit Ingredient Grade FunctionQuantity Formula Vasopressin, USP Active 3,000,000 Units 20 Units USPSodium USP Buffer 214.2 g 1.36 mg Acetate Trihydrate Sodium NF pHAdjustor 40 g QS to pH 3.8 Hydroxide Hydrochloric NF/EP pH Adjustor237.9 g QS to pH 3.8 Acid Chlorobutanol NF Preservative 0.8274 kg 5 mgWater for USP Solvent QS QS to 1 mL Injection Nitrogen NF Processing — —Aid

The 10 mL vasopressin formulation was compared to the guidelines forinactive ingredients provided by the Food and Drug Administration (FDA).The results are shown in TABLE 49 below.

TABLE 49 Vasopressin 10 Concen- Inactive Ingredients mL Formulationtration Guideline Acceptable Ingredient (mg/mL) (% w/v) Level Sodium1.36 0.136% IV (infusion); Acetate Injection 0.16% Trihydrate Sodium QSto pH 3.8 QS to pH 3.8 N/A Hydroxide Hydrochloric QS to pH 3.8 QS to pH3.8 N/A Acid Chlorobutanol 5 mg 0.5%  IV (Infusion); Injection 1% Waterfor QS to 1 mL QS to target N/A Injection volume

Example 14: Alternative Vasopressin Formulation for Clinical Use

A 1 mL dosage of vasopressin was prepared. A description of theformulation is shown in TABLE 50 below.

TABLE 50 Drug Product Description Vasopressin, USP Active Ingredient 20Units/mL (~0.04 mg) Dosage Form Injection — Route of Intravenous —Administration Description Clear colorless to practically — colorlesssolution supplied in a 3 mL vial with flip-off cap

The drug composition of the formulation is provided in TABLE 51.

TABLE 51 Drug Product Composition Ingredient Function Quantity (mg/mL)Vasopressin, USP Active 20 Units Sodium Acetate Trihydrate, USP Buffer1.36 Sodium Hydroxide NF/EP pH Adjustor QS for pH adjustment to pH 3.8Hydrochloric Acid, NF/EP pH Adjustor QS for pH adjustment to pH 3.8Water for Injection Solvent QS to 1 mL

The 1 mL vasopressin formulation was compared to the guidelines forinactive ingredients provided by the Food and Drug Administration (FDA).The results are shown in TABLE 52 below.

TABLE 52 Vasopressin 1 Concen- Inactive Ingredients mL Formulationtration Guideline Acceptable Ingredient (mg/mL) (% w/v) Level Sodium1.36 0.136% 0.16% Acetate Trihydrate Sodium QS to pH 3.8 QS to pH 3.8  8% Hydroxide Hydrochloric QS to pH 3.8 QS to pH 3.8  10% Acid Waterfor QS to 1 mL QS to target N/A Injection volume

Example 15: 15-Month Stability Data for Vasopressin Formulations

The drug product detailed in TABLE 51 was tested for stability over a15-month period. Three different lots (X, Y, and Z) of the vasopressindrug formulation were stored at 25° C. for 15 months in an upright orinverted position. At 0, 1, 2, 3, 6, 9, 12, 13, 14, and 15 months, theamount of vasopressin (AVP), % label claim (LC), amount of variousimpurities, and pH was measured. The vasopressin and impurity amountswere determined using the HPLC method described above in EXAMPLE 1. Theresults of the stability experiment are shown in TABLES 53-54 below.

TABLE 53 Inverted Storage of Vasopressin Formulations at 25° C. UI- UIUI- UI- UI- UI- UI- UI- D- 0.81- 0.97 1.02- 1.72- 1.81- 1.90- 2.05-2.09- AVP % Gly9 Glu4 Asn Asp5 Dimer Acetyl 0.86 0.99 1.03 1.76 1.891.96 2.07 2.10 Total Lot Month (U/mL) LC (%) (%) (%) (%) (%) (%) (%) (%)(%) (%) (%) (%) (%) (%) Impurities pH X 0 19.6 97.9 0.3 0.4 0.3 1.0 3.8Y 0 19.7 98.6 0.3 0.4 0.3 1.1 3.8 Z 0 19.9 99.3 0.1 0.5 0.2 0.8 3.8 X 119.6 98.1 0.2 0.2 0.1 0.4 0.4 0.3 1.6 3.8 Y 1 19.6 97.9 0.2 0.2 0.1 0.40.4 0.3 1.6 3.9 Z 1 19.8 99 0.2 0.2 0.6 0.1 0.2 1.4 3.8 X 2 19.6 98.10.3 0.3 0.1 0.3 0.4 0.3 1.7 3.7 Y 2 19.5 97.5 0.2 0.3 0.1 0.3 0.4 0.31.6 3.8 Z 2 19.8 99 0.3 0.4 0.5 0.2 1.3 3.8 X 3 19.6 97.8 0.4 0.5 0.10.1 0.3 0.4 0.4 2.2 Y 3 19.5 97.4 0.4 0.4 0.1 0.3 0.4 0.4 2.0 3.8 Z 319.7 98.6 0.4 0.4 0.5 0.3 1.6 X 6 19.3 96.5 0.7 0.8 0.1 0.2 0.3 0.4 0.42.9 3.8 Y 6 19.2 95.9 0.6 0.7 0.1 0.1 0.1 0.3 0.4 0.4 2.5 3.9 Z 6 19.698 0.6 0.7 0.1 0.5 0.2 2.3 3.9 X 9 19 95 1.0 1.0 0.2 0.3 0.4 0.4 0.1 3.6Y 9 18.9 94.5 0.8 1.0 0.2 0.3 0.4 0.4 0.1 3.1 3.9 Z 9 19.2 96 1.0 1.10.2 0.5 0.3 3.1 3.8 X 12 18.7 93.5 1.4 1.5 0.1 0.3 0.3 0.4 0.5 0.2 4.83.8 Y 12 18.6 93 1.1 1.2 0.2 0.2 0.3 0.4 0.5 0.3 0.2 4.4 3.8 Z 12 18.994.5 1.2 1.3 0.3 0.5 0.3 0.3 0.1 4.0 3.8 X 13 18.6 93 1.5 1.6 0.2 0.30.4 0.4 0.1 0.4 0.2 0.1 5.2 3.8 Y 13 18.5 92.5 1.2 1.3 0.2 0.3 0.3 0.40.1 0.5 0.1 0.4 0.2 0.2 5.2 3.9 Z 13 19 95 1.3 1.5 0.1 0.3 0.5 0.1 0.30.1 0.3 0.2 0.2 4.9 3.8 X 14 18.6 93 1.5 1.7 0.1 0.3 0.3 0.5 0.1 0.4 0.40.1 0.1 5.5 3.8 Y 14 18.5 92.5 1.2 1.4 0.1 0.3 0.3 0.5 0.1 0.4 0.5 0.20.2 5.3 3.9 Z 14 18.9 94.5 1.3 1.6 0.3 0.5 0.2 0.3 0.4 0.2 0.2 5.0 3.8 X15 18.5 92.5 1.6 1.8 0.1 0.4 0.3 0.4 0.1 0.4 0.3 0.2 0.2 5.9 3.8 Y 1518.4 92 1.3 1.5 0.1 0.3 0.3 0.4 0.1 0.4 0.5 0.3 0.1 5.3 3.9 Z 15 18.8 941.5 1.6 0.3 0.5 0.3 0.4 0.2 0.1 4.9 3.9

TABLE 54 Upright Storage of Vasopressin Formulations at 25° C. UI- UIUI- UI- UI- UI- UI- UI- D- 0.81- 0.97 1.02- 1.72- 1.81- 1.90- 2.05-2.09- AVP % Gly9 Glu4 Asn Asp5 Dimer Acetyl 0.86 0.99 1.03 1.76 1.891.96 2.07 2.10 Total Lot Month (U/mL) LC (%) (%) (%) (%) (%) (%) (%) (%)(%) (%) (%) (%) (%) (%) Impurities pH X 0 19.6 97.9 0.3 0.4 0.3 1.0 3.8Y 0 19.7 98.6 0.3 0.4 0.3 1.1 3.8 Z 0 19.9 99.3 0.1 0.5 0.2 0.8 3.8 X 119.6 98 0.2 0.2 0.1 0.3 0.4 0.3 1.6 3.8 Y 1 19.5 97.7 0.2 0.2 0.3 0.40.3 1.4 3.9 Z 1 19.7 98.3 0.2 0.2 0.6 0.2 1.2 3.8 X 2 19.6 98.2 0.3 0.30.3 0.4 0.3 1.6 3.7 Y 2 19.5 97.4 0.2 0.3 0.1 0.4 0.4 0.3 1.6 3.8 Z 219.8 99 0.3 0.3 0.5 0.2 1.3 3.8 X 3 19.5 97.6 0.4 0.4 0.1 0.3 0.4 0.42.1 3.7 Y 3 19.5 97.5 0.4 0.4 0.1 0.4 0.4 1.9 3.8 Z 3 19.7 98.7 0.4 0.40.1 0.5 0.3 1.7 X 6 19.3 96.5 0.7 0.8 0.1 0.2 0.3 0.4 0.4 2.9 3.8 Y 619.2 96 0.5 0.7 0.1 0.1 0.3 0.4 0.4 2.5 3.9 Z 6 19.5 97.5 0.7 0.7 0.20.5 0.3 2.3 3.9 X 9 18.9 94.5 1.0 1.1 0.2 0.3 0.4 0.2 0.1 3.7 3.8 Y 918.9 94.5 0.8 0.9 0.2 0.4 0.4 0.2 3.1 3.9 Z 9 19.2 96 0.9 1.0 0.2 0.50.3 2.9 3.8 X 12 18.6 93 1.4 1.5 0.1 0.3 0.3 0.4 0.5 0.2 0.1 4.8 3.7 Y12 18.7 93.5 1.1 1.2 0.1 0.3 0.3 0.4 0.5 0.2 0.2 4.6 3.9 Z 12 18.9 94.51.3 1.4 0.3 0.5 0.4 0.3 0.2 4.2 3.8 X 13 18.4 92 1.5 1.6 0.2 0.3 0.3 0.40.1 0.4 0.3 0.1 0.1 5.4 3.8 Y 13 18.6 93 1.1 1.3 0.2 0.3 0.3 0.4 0.1 0.40.3 0.2 4.6 3.9 Z 13 18.8 94 1.3 1.5 0.3 0.5 0.1 0.3 0.4 0.2 0.1 4.7 3.8X 14 18.6 93 1.5 1.7 0.1 0.4 0.3 0.4 0.1 0.4 0.3 0.1 5.4 3.8 Y 14 18.592.5 1.2 1.4 0.1 0.3 0.3 0.5 0.4 0.5 0.3 0.3 5.4 3.9 Z 14 18.8 94 1.31.5 0.3 0.5 0.1 0.3 0.5 0.2 0.2 5.0 3.8 X 15 18.4 92 1.6 1.8 0.1 0.4 0.30.4 0.1 0.4 0.3 0.2 5.7 3.8 Y 15 18.4 92 1.3 1.5 0.2 0.3 0.3 0.4 0.1 0.40.5 0.3 0.3 5.4 3.9 Z 15 18.6 93 1.5 1.6 0.3 0.5 0.2 0.4 0.2 0.3 5.1 3.9

The results from TABLES 53-54 indicate that stability of the vasopressinformulations was not significantly affected by either inverted orupright storage. The impurities detected included Gly9 (SEQ ID NO.: 2),Glu4 (SEQ ID NO.: 4), D-Asn (SEQ ID NO.: 10), Asp5 (SEQ ID NO.: 3),Acetyl-AVP (SEQ ID NO.: 7), vasopressin dimer, and several unidentifiedimpurities (UI). The unidentified impurities are labeled with a range ofrelative retention times at which the impurities eluted from the column.

The results indicate that the pH remained fairly constant over the15-month period, fluctuating between 3.8 and 3.9 throughout the 15months. The total impurities did not increase over 5.9%, and the % LC ofvasopressin did not decrease below 92%.

FIG. 19 shows a graph depicting the % LC over the 15-month study periodfor the results provided in TABLES 53-54. The starting amounts ofvasopressin were 97.9% LC for lot X, 98.6% LC for lot Y, and 99.3% LCfor lot Z. The results indicate that the % LC of vasopressin decreasedover the 15-month study period, but did not decrease below 92% LC.

The formula for the trend line of lot X was:

% LC=98.6−0.4262(month)

The formula for the trend line of lot Y was:

% LC=98.47−0.4326(month)

The formula for the trend line of lot Z was:

% LC=99.54−0.3906(month)

Example 16: 10 mL Vasopressin Formulation

The drug product description for a 10 mL vasopressin formulation isshown in TABLE 55 below:

TABLE 55 Drug Product Description Vasopressin, USP Active IngredientStrength 20 U/mL Dosage Form Injection Route of IntravenousAdministration Description Clear colorless to practically colorlesssolution supplied in a 10 mL vial with orange flip-off cap

The composition of the 10 mL vasopressin formulation is shown in TABLE56 below:

TABLE 56 Drug Product Composition Batch Unit Ingredient Grade FunctionQuantity Formula Vasopressin, USP Active 3,000,000 Units 20 Units USPSodium USP Buffer 214.2 g 1.36 mg Acetate Trihydrate Sodium NF pHAdjustor 40 g QS to pH 3.8 Hydroxide Hydrochloric NF/EP pH Adjustor237.9 g QS to pH 3.8 Acid Chlorobutanol NF Preservative 0.8274 kg 5 mgWater for USP Solvent QS QS to 1 mL Injection Nitrogen NF Processing — —Aid

The container closure system used in the 10 mL vasopressin formulationis shown below in TABLE 57.

TABLE 57 Container/Closure Description Part Type Vial 10 mL, 13 mm Type1, Flint (clear) tubing vial Stopper 13 mm, Westar RS, 4432/50 FlurotecCap Flip-Off Cap, 13 mm Orange Peel

Labeled vials containing the 10 mL vasopressin formulation are packagedinto secondary packaging consisting of preprinted paperboard cartons.The vials can be packaged in a single pack (one vial in one carton) or a5-pack (5 vials in one carton).

FIG. 20 below shows a diagram of a cap to be used on a vial describedherein. The left part of FIG. 20 shows an aluminum seal to be used in acap of the vial described herein. The height of seal is from about 6.17mm to about 6.38 mm. The middle of FIG. 20 shows the plastic button,which has a diameter of about 14.99 mm. The right portion of FIG. 20depicts the assembled cap with the aluminum seal placed on top of theplastic button. The assembled cap has a height from about 7.62 mm toabout 8.38 mm.

FIG. 21 depicts a stopper to be used in a vial described herein. Theleft part of FIG. 21 shows a top view, the center of FIG. 21 shows across-sectional side view, and the right part of FIG. 21 shows a bottomview of the stopper. FIG. 21 indicates that the diameter of the stoppercan be about 12.75±0.3 mm. The width of the top part of the stopper canbe about 2.11±0.3 mm. The height of the entire stopper can be about6.3±0.51 mm.

A vial for use in storing the 10 mL vasopressin formulation is shown inFIG. 22. The dimensions for the vial are shown in TABLE 58 below:

TABLE 58 Dimension as denoted in FIG. 22 Length (mm) d1 23.75 ± 0.25  d213.15 ± 0.2  d4 7.05 ± 0.2  d59 1 (minimum) h1  50 ± 0.5 h3 8.5 ± 0.5h21 3.9 ± 0.2 c51 35 (approximately) s1  1.2 ± 0.05 s2 0.7 (max) t 0.76(max)

Example 17: Container Closure Integrity Test for the 10 mL VasopressinFormulation

Microbial ingress testing can be performed to demonstrate containerclosure system seal integrity for a stopper used in a vial describedherein. Microbial ingress testing can evaluate the adequacy of theclosure to maintain a sterile barrier. A sample of the container closuresystem was tested by immersing media filled containers into a media bathchamber inoculated with a high concentration of Brevundimonas diminuta,which containers were then subjected to pressure and vacuum. Thecontainers were then removed from the pressure and vacuumed, incubated,and examined for bacterial growth.

Seventy-four washed and depyrogenated 10 mL tubing vials werehand-filled with approximately 5 mL of Trypticase Soy Broth and thenhand stoppered. The vials were then capped, and incubated at 20-25° C.for seven days and then at 30-35° C. for eight days. At the end of theincubation period, none of the vials had any microbial growth.

From the original 74 vials, 20 vials were sent for microbial ingresstesting, along with three positive controls and two negative controls.The test vials and positive controls were submerged in a bacterialsuspension. The two negative controls were not exposed to the bacterialsuspension, vacuum, or pressure, but were incubated for seven days at30-35° C. The test vial samples were then incubated at 30-35° C. forseven days, and the positive controls were incubated at 30-35° C. forfive days. At the end of the incubation intervals, all the samples wereexamined for evidence of microbial ingress by assessing the turbidity ofthe solutions. There was no microbial growth in 20 out of 20 of the testsamples, nor was there growth in the negative controls. There wasbacterial growth in 3 out of 3 of the positive controls.

Example 18: Formulation Stability for 10 mL Vasopressin Formulation

Three batches of the 10 mL vasopressin formulation were tested forstability at 2-8° C. and 25° C. for three months. The formulation usedfor the tests is shown in TABLE 56 above. The study layout is shown inTABLE 59 below. Lots A-C were the 10 mL vasopressin formulation, whileLots D-F were the 1 mL vasopressin formulation.

TABLE 59 Condition Study Lot ° C. % RH Orientation Study Duration 1 A 5Not Defined Inverted 24 months 2 A 5 Not Defined Upright 24 months 3 A25 60 Inverted 6 months 4 A 25 60 Upright 6 months 1 B 5 Not DefinedInverted 24 months 2 B 5 Not Defined Upright 24 months 3 B 25 60Inverted 6 months 4 B 25 60 Upright 6 months 1 C 5 Not Defined Inverted24 months 2 C 5 Not Defined Upright 24 months 3 C 25 60 Inverted 6months 4 C 25 60 Upright 6 months 1 D 5 Not Defined Inverted 24 months 2D 5 Not Defined Upright 24 months 3 D 25 60 Inverted 24 months 4 D 25 60Upright 24 months 1 E 5 Not Defined Inverted 24 months 2 E 5 Not DefinedUpright 24 months 3 E 25 60 Inverted 24 months 4 E 25 60 Upright 24months 1 F 5 Not Defined Inverted 24 months 2 F 5 Not Defined Upright 24months 3 F 25 60 Inverted 24 months 4 F 25 60 Upright 24 months

The stability trends were calculated from a linear regression of thedatasets. The estimated shelf-life (ESL) provided in the tables belowrefers to the shortest time in months at which the extrapolated 95%confidence interval for the linear model of the attribute in questionexceeded the specification limit. All models assumed aconcentration-independent linear decline or increase (zero-ordermodels). The results were pooled to obtain the best estimates foraverage trends. Three linear degradation models were fit to the data andthe expiration date of the batches was estimated following FDA-issuedguidelines. The three models were the following:

-   -   Model 1: Different slopes and different intercepts for the        batches.    -   Model 2: Common slope and different intercepts for the batches.    -   Model 3: Common slope and common intercept for the batches.

The recommended model was determined by the following procedure: Model 1was fit with the time effect first in the model, followed by the batcheffect, then the interaction. Using Type I (Sequential) sums-of-squares,the regressions were tested for equal slopes (Source C in the output).If the p-value was less than 0.25, the slopes were assumed to bedifferent across batches. Then, the procedure was stopped and Model 1was used to estimate the expiration date. If the p-value was greaterthan or equal to 0.25, the slopes were assumed to be common acrossbatches. Then, the procedure continued to step 2. If the conclusion fromstep 1 was common slopes, then the regressions were tested for equalintercepts using Type I (Sequential) sums-of-squares from Model 1(Source B in the output). If the p-value was less than 0.25, theintercepts were assumed to be different across batches, and Model 2 wasused to estimate the expiration date. If the p-value was greater than orequal to 0.25, the intercepts were assumed to be common across batches,and Model 3 was used to estimate the expiration date. When Model 1(different slopes and different intercepts) was used for estimating theexpiration date, the MSE (mean squared error) was not pooled acrossbatches. Prediction intervals were computed for each batch usingindividual mean squared errors, and the interval that crossed thespecification limit first was used to estimate the expiration date.

The results indicated that the pH of the formulations ranged from 3.7 to3.8, and no significant changes were observed through three months underlong-term and accelerated storage conditions. The vasopressin assayvalues ranged from 100% to 100.3% at the time of study release. Theresults at all stability intervals through three months were within theproposed limits as shown in the data tables below. The stability studyresults for the 10 mL vasopressin formulation were compared to the 1 mLvasopressin formulation and are shown TABLE 60 below.

At 25° C., the shortest estimated shelf-life based on trendextrapolation at 25° C. was approximately 17.2 months, which wascomparable to the 15.1 month shelf-life value obtained for the 1 mLvasopressin formulation as shown in TABLE 60.

At 5° C., the vasopressin assay ranged from 99.8% to 100.1% after threemonths.

TABLE 60 Intercept ± Slope ± ESL Std. Error Std. Error Model FormulationR² Lot (months) (%) (%/month) Type 10 mL 0.7 A 17.2  100% ± −0.46% ±Common B 0.12% 0.06% slopes/ C common intercepts  1 mL 0.97 D 15.1 98.6%± −0.53% ± Common 0.27% 0.02% slopes/ E 99.1% ± different 0.27%intercepts F 99.6% ± 0.27% Note: For this regression analysis, uprightand inverted studies were treated as independent replicates of a singlebatch.

FIG. 23 shows the vasopressin assay results (represented as % labelclaim) of the studies performed at 25° C. with upright storage. Thelinear equation for each of the lots was as follows:

% LC=100−0.42(month)  Lot A

% LC=99.86−0.44(month)  Lot B

% LC=100−0.4(month)  Lot C

% LC=98.58−0.5359(month)  Lot D

% LC=98.58−0.5359(month)  Lot E

% LC=99.37−0.515(month)  Lot F

FIG. 24 shows the vasopressin assay results (represented as % labelclaim) of the studies performed at 25° C. with inverted storage. Thelinear equation for each of the lots was as follows:

% LC=99.8−0.4(month)  Lot A:

% LC=99.97−0.63(month)  Lot B

% LC=100−0.46(month)  Lot C

% LC=98.68−0.5519(month)  Lot D

% LC=100−0.5634(month)  Lot E

% LC=99.49−0.52(month)  Lot F

The data supported a 24-month refrigerated (2-8° C.) shelf life with a12-month period out of refrigeration.

Vasopressin impurities, as detailed in TABLE 1, were tested for in the 1mL and 10 mL vasopressin formulations. First, Gly9-AVP was measured inthe formulations after storage for three months. Gly9-AVP is adeamidation product and major degradant of vasopressin. Theconcentration of Gly9-AVP was around <0.10% to 0.1% at time of release.The results at all stability intervals through three months were withinthe proposed limits (NMT 6%) as shown in TABLE 61 below.

TABLE 61 Intercept ± Slope ± ESL Std. Error Std. Error Model FormulationR² Lot (months) (%) (%/month) Type 10 mL 0.9 A 49.9   0.15% ± 0.10% ±Common 0.02% 0.0% slopes/ B    0.1% ± different 0.02% intercepts C   0.1% ± 0.02%  1 mL 0.99 D 32.2 −0.03% ± 0.19% ± Different 0.06% 0.0%slopes/ E −0.05% ± 0.18% ± different 0.06% 0.0% intercepts −0.04% ±0.19% ± F 0.06% 0.0% Note: For this regression analysis, upright andinverted studies are treated as independent replicates of a singlebatch.

The stability study results for the 10 mL vasopressin formulations werecompared to the 1 mL vasopressin formulation and plotted as shown inFIGS. 25 and 26. FIG. 25 shows the amount of Gly9-AVP when theformulations were stored at 25° C. in an upright position. The linearequation for each of the lots was as follows:

Y=0.0015+0.001(month)  Lot A

Y=0.001+0.001(month)  Lot B

Y=0.001+0.001(month)  Lot C

Y=−0.000204+0.001825(month)  Lot D

Y=−0.000204+0.001825(month)  Lot E

Y=−0.000545+0.0019(month)  Lot F

FIG. 26 shows the amount of Gly9-AVP when the formulations were storedat 25° C. in an inverted position. The linear equation for each of thelots was as follows:

Y=0.0015+0.001(month)  Lot A

Y=0.001+0.001(month)  Lot B

Y=0.001+0.001(month)  Lot C

Y=−0.000431+0.001875(month)  Lot D

Y=−0.000743+0.001794(month)  Lot E

Y=−0.000234+0.001814(month)  Lot F

The regression analysis and trend estimates for stability at 25° C. areshown above in TABLE 61. As indicated by the trend analysis and FIGS. 25and 26, the trends in assay were well-represented by linear zero-orderregression models. At the 25° C. conditions, the results did not poolintercepts but did pool slopes for the new formulation. The slope forthis model was about 0.10%/month. The shortest estimated shelf-lifebased on trend extrapolation at 25° C. was about 49.9 months. This was a17.7 month improvement compared to the 32.2 month value obtained fromthe 1 mL vasopressin results at 25° C. At 5° C., the vasopressin assayresults were all 0.1% to 0.2% after 3 months.

Next, Glu4-AVP was measured in the formulations after storage for threemonths. Glu4-AVP is a deamidation product and major degradant ofvasopressin. The concentration of Gly9-AVP was around <0.10% to 0.1% attime of release. The results at all stability intervals through threemonths were within the proposed limits (NMT 6%) as shown in TABLE 62below.

TABLE 62 Intercept ± Slope ± ESL Std. Error Std. Error Model FormulationR² Lot (months) (%) (%/month) Type 10 mL 0.94 A 34   0.12% ± 0.15% ±Different 0.03% 0.01% slopes/ B   0.11% ± 0.14% ± different 0.03% 0.01%intercepts C   0.13% ± 0.11% ± 0.03% 0.01%  1 mL 0.99 D 28.7 −0.05% ±0.21% ± Pooled E 0.0% 0.0% slopes/ F Pooled intercepts

The stability study results for the 10 mL vasopressin formulations werecompared to the 1 mL vasopressin formulation and plotted as shown inFIGS. 27 and 28. FIG. 27 shows the amount of Glu4-AVP when theformulations were stored at 25° C. in an upright position. The linearequation for each of the lots was as follows:

Y=0.0013+0.0013(month)  Lot A

Y=0.0013+0.0013(month)  Lot B

Y=0.0012+0.0012(month)  Lot C

Y=−8.383×10⁻⁵+0.002036(month)  Lot D

Y=−8.383×10⁻⁵+0.002036(month)  Lot E

Y=−0.001102+0.002163(month)  Lot F

FIG. 28 shows the amount of Glu4-AVP when the formulations were storedat 25° C. in an inverted position. The linear equation for each of thelots was as follows:

Y=0.0011+0.0016(month)  Lot A

Y=0.0009+0.0014(month)  Lot B

Y=0.0014+0.0009(month)  Lot C

Y=−0.000599+0.002114(month)  Lot D

Y=−0.000826+0.001997(month)  Lot E

Y=−0.000473+0.00206(month)  Lot F

The regression analysis and trend estimates for stability at 25° C. areshown above in TABLE 62. As indicated by the trend analysis and FIGS. 27and 28, the trends in assay were well-represented by linear zero-orderregression models. At the 25° C. conditions, the results did not poolintercepts or slopes for the 10 mL vasopressin formulation. The slopesfor this model are from about 0.11% to 0.15% per month. The shortestestimated shelf-life based on trend extrapolation at 25° C. was about 34months. This was a 5.3 month improvement compared to the 28.7 monthvalue obtained from the 1 mL vasopressin results at 25° C. At 5° C., thevasopressin assay results were all 0.1% to 0.2% after 3 months.

The test results for D-Asn-AVP met the acceptance criteria (NMT 1%) atall conditions and intervals through three months on long-term, andaccelerated, stability. All the results for D-Asn-AVP ranged from nonedetected to 0.1%. No significant changes were observed through threemonths under long-term and accelerated storage conditions.

The test results for Asp5-AVP met the acceptance criteria (NMT 1.5%) atall conditions and intervals through three months on long-term, andaccelerated, stability. All the results for Asp5-AVP ranged from nonedetected to 0.1%. No significant changes were observed through threemonths under long-term and accelerated storage conditions.

The test results for AVP-Dimer met the acceptance criteria (NMT 1%) atall conditions and intervals through three months on long-term, andaccelerated, stability. All the results for AVP-Dimer were nonedetected. No significant changes were observed through three monthsunder long-term and accelerated storage conditions.

The test results for Acetyl-AVP met the acceptance criteria (NMT 1%) atall conditions and intervals through three months on long-term, andaccelerated, stability. All the results for Acetyl-AVP ranged from 0.3%to 0.6%. No significant changes were observed through three months underlong-term and accelerated storage conditions.

The test results for individual unidentified impurities met theacceptance criteria (NMT 1%) at all conditions and intervals throughthree months on long-term, and accelerated, stability. All unidentifiedimpurities ranged from none detected to 0.4%. No significant changeswere observed through three months under long-term and acceleratedstorage conditions.

The acceptance criteria for total impurities was NMT 17%. The totalimpurities included the sum of all identified and unidentifiedimpurities. The values for total impurities were consistently low (1% to1.2%) at the time of release. The results at all stability intervalsthrough three months were within the proposed limits as shown in TABLE63 below.

TABLE 63 Intercept ± Slope ± ESL Std. Error Std. Error Model FormulationR² Lot (months) (%) (%/month) Type 10 mL 0.88 A 52.3 1.07% ± 0.26% ±Pooled 0.06% 0.02% slopes/ B 1.29% ± different 0.06% intercepts C 1.26%± 0.06%  1 mL 0.98 D 32.3 0.67% ± 0.49% ± Pooled E 0.15% 0.01% slopes/ FPooled intercepts

The stability study results for the 10 mL vasopressin formulations werecompared to the 1 mL vasopressin formulation and plotted as shown inFIGS. 29 and 30. FIG. 29 shows the total impurities when theformulations were stored at 25° C. in an upright position. The linearequation for each of the lots was as follows:

Y=0.0108+0.0023(month)  Lot A

Y=0.0126+0.0026(month)  Lot B

Y=0.0123+0.0028(month)  Lot C

Y=0.005617+0.004926(month)  Lot D

Y=0.005617+0.004926(month)  Lot E

Y=−0.008521+0.004824(month)  Lot F

FIG. 30 shows the amount of total impurities when the formulations werestored at 25° C. in an inverted position. The linear equation for eachof the lots was as follows:

Y=0.011+0.0025(month)  Lot A

Y=0.0131+0.0026(month)  Lot B

Y=0.0125+0.0025(month)  Lot C

Y=0.006132+0.005015(month)  Lot D

Y=0.006383+0.004907(month)  Lot E

Y=0.008467+0.004705(month)  Lot F

The regression analysis and trend estimates for stability at 25° C. areshown above in TABLE 63. As indicated by the trend analysis and FIGS. 29and 30, the trends in assay were well-represented by linear zero-orderregression models. At the 25° C. conditions, the results did not poolintercepts and did pool slopes for the 10 mL vasopressin formulation.The slopes for this pooled model is about 0.26% per month. The shortestestimated shelf-life based on trend extrapolation at 25° C. was about52.3 months. This was a 20 month improvement compared to the 32.3 monthvalue obtained from the 1 mL vasopressin results at 25° C. At 5° C., thevasopressin assay results were all 1% to 1.5% after 3 months.

The test results met the specification requirements for particulatematter under all study conditions. The highest reported values wereabout 13 counts (greater than 10 microns) and 1 count (greater than 25microns).

The test results passed the bacterial endotoxin test, for which theacceptance criteria was NMT 29 EU/mL.

The test results passed the sterility test.

Overall, the data supported a 24-month refrigerated (2-8° C.) shelf lifewith a 12-month period out of refrigeration room temperature storage. Asummary of the estimated shelf life for the measured vasopressinattributed is shown in TABLE 64 below.

TABLE 64 Estimated out of Estimated out of Refrigerator StorageRefrigerator Storage Trending Period (months) 10 mL Period (months) 1 mLCQA formulation formulation Vasopressin 17.2 15.1 Glu4-AVP 34 28.7Gly9-AVP 49.9 32.2 Total 52.3 32.3 Impurities

TABLES 65-76 provide the raw data for the different measured attributesof the 10 mL vasopressin formulations at 5° C. and 25° C./60% relativehumidity.

TABLE 65 Lot A, Inverted, 5° C. Test Acceptance Criteria Initial Amount3 months Assay 90%-110% LC 100.3%  100.1%  Related Substances Gly9-AVPNMT 6% 0.1% 0.2% Glu4-AVP NMT 6% 0.1% 0.2% D-Asn-AVP NMT 1% ND NDAsp5-AVP NMT 1.5% ND ND AVP-Dimer NMT 1% ND ND Acetyl-AVP NMT 1% 0.6%0.6% Unidentified NMT 1% RRT 0.84 = <0.1%  RRT 0.1 = <0.1% RRT 1.03 =0.2%  RRT 0.11 = <0.1% RRT 0.37 = <0.1% RRT 0.83 = <0.1% RRT 1.03 =0.2%  Total Impurities NMT 17%   1% 1.2% Chlorobutanol 0.4%-0.6% w/v0.5%  0.49% pH 2.5-4.5 3.8  3.7 

TABLE 66 Lot A, Upright, 5° C. Test Acceptance Criteria Initial Amount 3months Assay 90%-110% LC 100.3%  99.8%  Related Substances Gly9-AVP NMT6% 0.1% 0.2% Glu4-AVP NMT 6% 0.1% 0.2% D-Asn-AVP NMT 1% ND ND Asp5-AVPNMT 1.5% ND ND AVP-Dimer NMT 1% ND ND Acetyl-AVP NMT 1% 0.6% 0.6%Unidentified NMT 1% RRT 0.84 = <0.1% RRT 0.11 = <0.1% RRT 1.03 = 0.2% RRT 0.83 = <0.1% RRT 1.03 = 0.2%  Total Impurities NMT 17%   1% 1.3%Chlorobutanol 0.4%-0.6% w/v 0.5%  0.49% pH 2.5-4.5 3.8  3.8 

TABLE 67 Lot A, Inverted, 25° C./60% RH Initial Test Acceptance CriteriaAmount 1 month 2 months 3 months Assay 90%-110% LC 100.3%  98.7%  98.9% 98.9%  Related Gly9-AVP NMT 0.1% 0.3% 0.4% 0.4% Substances 6% Glu4-AVPNMT 0.1% 0.3% 0.4% 0.6% 6% D-Asn-AVP NMT ND ND ND <0.1%   1% Asp5-AVPNMT ND ND <0.1%   <0.1%   1.5%   AVP-Dimer NMT ND ND ND ND 1% Acetyl-AVPNMT 0.6% 0.6% 0.6% 0.6% 1% Unidentified NMT RRT 0.84 = RRT 0.84 = RRT0.11 =  RRT 0.8 = 1% <0.1%   <0.1%   <0.1%   <0.1%   RRT 1.03 = RRT1.7 + RRT 0.83 = 1.6 = 0.2% <0.1%   <0.1%   <0.1%   RRT 1.03 = RRT 1.03= RRT 1.03 = 0.3% 0.2% 0.2% Total NMT   1% 1.5% 1.6% 1.8% Impurities17%  Chlorobutanol 0.4%-0.6% w/v 0.5% 0.49%  0.49%  0.49%  pH 2.5-4.53.8 3.7 3.7 3.7

TABLE 68 Lot A, Upright, 25° C./60% RH Initial Test Acceptance CriteriaAmount 1 month 2 months 3 months Assay 90%-110% LC 100.3%  99.4%  98.8% 99.1%  Related Gly9-AVP NMT 0.1% 0.3% 0.4% 0.4% Substances 6% Glu4-AVPNMT 0.1% 0.3% 0.4% 0.5% 6% D-Asn-AVP NMT ND ND ND <0.1%   1% Asp5-AVPNMT ND ND <0.1%   <0.1%   1.5%   AVP-Dimer NMT ND ND ND ND 1% Acetyl-AVPNMT 0.6% 0.6% 0.6% 0.6% 1% Unidentified NMT RRT 0.84 = RRT 0.84 = RRT0.11 =  RRT 0.8 = 1% <0.1%   <0.1%   <0.1%   <0.1%   RRT 1.03 = RRT1.7 + RRT 0.83 = 1.6 = 0.2% <0.1%   <0.1%   <0.1%   RRT 1.03 = RRT 1.03= RRT 1.03 = 0.3% 0.2% 0.2% Total NMT   1% 1.4% 1.6% 1.7% Impurities17%  Chlorobutanol 0.4%-0.6% w/v 0.5% 0.49%  0.49%  0.49%  pH 2.5-4.53.8 3.7 3.7 3.7

TABLE 69 Lot B, Inverted, 5° C. Test Acceptance Criteria Initial Amount3 months Assay 90%-110% LC 100%  99.8%  Related Substances Gly9-AVP NMT6% <0.1%  0.2% Glu4-AVP NMT 6% 0.1% 0.2% D-Asn-AVP NMT 1% 0.1% 0.1%Asp5-AVP NMT 1.5% ND ND AVP-Dimer NMT 1% ND ND Acetyl-AVP NMT 1% 0.3%0.4% Unidentified NMT 1% RRT 0.84 = 0.4%  RRT 0.11 = <0.1% RRT 1.03 =0.3% RRT 0.83 = 0.4% RRT 1.03 = 0.3% Total Impurities NMT 17% 1.2% 1.5%Chlorobutanol 0.4%-0.6% w/v  0.49%  0.47% pH 2.5-4.5 3.8  3.8 

TABLE 70 Lot B, Upright, 5° C. Test Acceptance Criteria Initial Amount 3months Assay 90%-110% LC 100%  100%  Related Substances Gly9-AVP NMT 6%<0.1%  0.1% Glu4-AVP NMT 6% 0.1% 0.1% D-Asn-AVP NMT 1% 0.1% 0.1%Asp5-AVP NMT 1.5% ND ND AVP-Dimer NMT 1% ND ND Acetyl-AVP NMT 1% 0.3%0.4% Unidentified NMT 1% RRT 0.84 = 0.4%  RRT 0.11 = <0.1% RRT 1.03 =0.3% RRT 0.83 = 0.4% RRT 1.03 = 0.4% Total Impurities NMT 17% 1.2% 1.5%Chlorobutanol 0.4%-0.6% w/v  0.49%  0.47% pH 2.5-4.5 3.8  3.8 

TABLE 71 Lot B, Inverted, 25° C./60% RH Initial Test Acceptance CriteriaAmount 1 month 2 months 3 months Assay 90%-110% LC  100%  99.2%  98.9%  98% Related Gly9-AVP NMT <0.1%   0.2% 0.3% 0.4% Substances 6% Glu4-AVPNMT 0.1% 0.2% 0.4% 0.5% 6% D-Asn-AVP NMT 0.1% ND ND 0.1% 1% Asp5-AVP NMTND ND <0.1%   <0.1%   1.5%   AVP-Dimer NMT ND 0.2% ND ND 1% Acetyl-AVPNMT 0.3% 0.3% 0.4% 0.3% 1% Unidentified NMT RRT 0.84 = RRT 0.84 = RRT0.11 =  RRT 0.83 = 1% 0.4% 0.4% <0.1%   0.4% RRT 1.03 = RRT 1.03 = RRT0.83 = RRT 0.9 = 0.3% 0.4% 0.4% <0.1%   RRT 1.03 = RRT 1.6 = 0.3% 0.1%RRT 1.03 = 0.3% Total NMT 1.2% 1.8% 1.7% 2.1% Impurities 17% Chlorobutanol 0.4%-0.6% w/v 0.49%  0.49%  0.48%  0.48%  pH 2.5-4.5 3.83.7 3.7 3.8

TABLE 72 Lot B, Upright, 25° C./60% RH Initial Test Acceptance CriteriaAmount 1 month 2 months 3 months Assay 90%-110% LC  100%  99.1%  99.2% 98.5%  Related Gly9-AVP NMT <0.1%   0.2% 0.3% 0.4% Substances 6%Glu4-AVP NMT 0.1% 0.3% 0.4% 0.5% 6% D-Asn-AVP NMT 0.1% ND <0.1%   0.1%1% Asp5-AVP NMT ND ND <0.1%   <0.1%   1.5%   AVP-Dimer NMT ND ND ND ND1% Acetyl-AVP NMT 0.3% 0.3% 0.4% 0.3% 1% Unidentified NMT RRT 0.84 = RRT0.84 = RRT 0.11 = RRT 0.8 = 1% 0.4% 0.4% <0.1%   0.4% RRT 1.03 = RRT1.03 = RRT 0.83 = RRT 1.6 = 0.3% 0.4% 0.4% <0.1%   RRT 1.03 = 0.3% RRT1.56 = <0.1%   Total NMT 1.2% 1.6% 1.8%   2% Impurities 17% Chlorobutanol 0.4%-0.6% w/v 0.49%  0.49%  0.48%  0.48%  pH 2.5-4.5 3.83.8 3.7 3.8

TABLE 73 Lot C, Inverted, 5° C. Test Acceptance Criteria Initial Amount3 months Assay 90%-110% LC 100.3%  100%  Related Substances Gly9-AVP NMT6% <0.1%  0.2% Glu4-AVP NMT 6% 0.1% 0.1% D-Asn-AVP NMT 1% ND 0.1%Asp5-AVP NMT 1.5% ND ND AVP-Dimer NMT 1% ND ND Acetyl-AVP NMT 1% 0.3%0.4% Unidentified NMT 1% RRT 0.84 = 0.4% RRT 0.11 = <0.1% RRT 1.03 =0.3% RRT 0.59 = <0.1% RRT 0.83 = 0.4%  RRT 1.03 = 0.4%  Total ImpuritiesNMT 17% 1.1% 1.5% Chlorobutanol 0.4%-0.6% w/v  0.49%  0.48% pH 2.5-4.53.8  3.8 

TABLE 74 Lot C, Upright, 5° C. Test Acceptance Criteria Initial Amount 3months Assay 90%-110% LC 100.3%  100.1%  Related Substances Gly9-AVP NMT6% <0.1%  0.2% Glu4-AVP NMT 6% 0.1% 0.1% D-Asn-AVP NMT 1% ND 0.1%Asp5-AVP NMT 1.5% ND ND AVP-Dimer NMT 1% ND ND Acetyl-AVP NMT 1% 0.3%0.4% Unidentified NMT 1% RRT 0.84 = 0.4%  RRT 0.11 = <0.1% RRT 1.03 =0.3% RRT 0.83 = 0.4% RRT 1.03 = 0.4% Total Impurities NMT 17% 1.1% 1.5%Chlorobutanol 0.4%-0.6% w/v  0.49%  0.48% pH 2.5-4.5 3.8  3.7 

TABLE 75 Lot C, Inverted, 25° C./60% RH Initial Test Acceptance CriteriaAmount 1 month 2 months 3 months Assay 90%-110% LC 100.3%  99.2%  99.1% 98.8%  Related Gly9-AVP NMT <0.1%   0.2% 0.3% 0.4% Substances 6%Glu4-AVP NMT 0.1% 0.3% 0.3% 0.4% 6% D-Asn-AVP NMT ND 0.1% <0.1%   0.1%1% Asp5-AVP NMT ND ND <0.1%   <0.1%   1.5%   AVP-Dimer NMT ND ND ND ND1% Acetyl-AVP NMT 0.3% 0.3% 0.4% 0.3% 1% Unidentified NMT RRT 0.84 = RRT0.84 = RRT 0.11 = RRT 0.8 = 1% 0.4% 0.4% <0.1%   0.4% RRT 1.03 = RRT1.03 = RRT 0.83 = RRT 1 =   0.3% 0.4% 0.4% 0.3% RRT 1.03 = RRT 1.6 =0.3% <0.1%   Total NMT 1.1% 1.7% 1.8% 1.9% Impurities 17%  Chlorobutanol0.4%-0.6% w/v 0.49%  0.49%  0.49%  0.49%  pH 2.5-4.5 3.8 3.7 3.7 3.8

TABLE 76 Lot C, Upright, 25° C./60% RH Initial Test Acceptance CriteriaAmount 1 month 2 months 3 months Assay 90%-110% LC 100.3%  99.1%  99.3% 98.9%  Related Gly9-AVP NMT <0.1%   0.2% 0.3% 0.4% Substances 6%Glu4-AVP NMT 0.1% 0.3% 0.3% 0.5% 6% D-Asn-AVP NMT ND 0.1% <0.1%   0.1%1% Asp5-AVP NMT ND ND <0.1%   <0.1%   1.5%   AVP-Dimer NMT ND ND ND ND1% Acetyl-AVP NMT 0.3% 0.3% 0.4% 0.3% 1% Unidentified NMT RRT 0.84 = RRT0.84 = RRT 0.11 = RRT 0.8 = 1% 0.4% 0.4% <0.1%   0.4% RRT 1.03 = RRT1.03 = RRT 0.83 = RRT 1 =   0.3% 0.4% 0.4% 0.3% RRT 1.03 = RRT 1.6 =0.3% <0.1% Total NMT 1.1% 1.7% 1.8%   2% Impurities 17%  Chlorobutanol0.4%-0.6% w/v 0.49%  0.49%  0.49%  0.49% Ph 2.5-4.5 3.8 3.7 3.7 3.8

Example 19: Illustrative Regimen for Therapeutic Use of a 10 mLVasopressin Formulation

Vasopressin is indicated to increase blood pressure in adults withvasodilatory shock (for example, adults who are post-cardiotomy orseptic) who remain hypotensive despite fluids and catecholamines.

Preparation and Use of Vasopressin.

Dilute vasopressin with normal saline (0.9% sodium chloride) or 5%dextrose in water (D5W) to either 0.1 units/mL or 1 unit/mL forintravenous administration. Discard unused diluted solution after 18hours at room temperature or 24 hours under refrigeration.

Vasopressin is prepared according to TABLE 77 below:

TABLE 77 Mix Fluid Restriction? Final Concentration Vasopressin DiluentNo 0.1 units/mL 2.5 mL (50 units) 500 mL Yes 1 unit/mL 5 mL (100 units)100 mL

Diluted vasopressin should be inspected for particulate matter anddiscoloration prior to use whenever solution and container permit.

The goal of treatment with vasopressin is optimization of perfusion tocritical organs, but aggressive treatment can compromise perfusion oforgans, like the gastrointestinal tract, for which function is difficultto monitor.

For post-cardiotomy shock, a dose of 0.03 units/minute is used as astarting point. For septic shock, a dose of 0.01 units/minute is used asa starting point. If the target blood pressure response is not achieved,the dose is titrated up by 0.005 units/minute at 10- to 15-minuteintervals. The maximum dose for post-cardiotomy shock is 0.1units/minute and for septic shock 0.07 units/minute. After target bloodpressure has been maintained for 8 hours without the use ofcatecholamines, the vasopressin can be tapered by 0.005 units/minuteevery hour as tolerated to maintain target blood pressure.

Vasopressin is provided as an injection at 20 units/mL. Vasopressin issupplied in vials as follows:

-   -   A carton of 25 multiple dose vials each containing 1 mL        vasopressin each at 20 units/mL of vasopressin.    -   A carton of 1 multiple dose vial containing 10 mL vasopressin at        20 units/mL.    -   A carton of 5 multiple dose vials each containing 10 mL        vasopressin at 20 unit/mL of vasopressin.

Vasopressin is stored between 2-8° C., and is not to be frozen.

The vasopressin vials can be held up to 12 months upon removal fromrefrigeration to room temperature storage conditions (20-25° C.),anytime within the labeled shelf life. Once removed from refrigeration,unopened vials should be marked to indicate the revised 12 monthexpiration date. If the original expiration date is shorter than therevised expiration date, then the shorter date should be used.

The 1 mL vial should be discarded 48 hours after the first puncture. The10 mL vial can be discarded 30 days after the first puncture. Thestorage conditions and expiration periods are summarized in TABLE 78below:

TABLE 78 Unopened Unopened Room Temperature Opened Refrigerated (20-25°C.; do not store (after first (2-8° C.) above 25° C.) puncture) 1 mLvial Until printed 12 months or until printed 48 hours expiration dateexpiration date, whichever is earlier 10 mL vial Until printed 12 monthsor until printed 30 days expiration date expiration date, whichever isearlier

Contraindications, Adverse Reactions, and Drug-Drug Interactions.

Vasopressin is contraindicated in patients with known allergy orhypersensitivity to 8-L-arginine vasopressin or chlorobutanol.Additionally, use of vasopressin in patients with impaired cardiacresponse can worsen cardiac output.

Adverse reactions have been observed with the use of vasopressin, whichadverse reactions include bleeding/lymphatic system disorders,specifically, hemorrhagic shock, decreased platelets, intractablebleeding; cardiac disorders, specifically, right heart failure, atrialfibrillation, bradycardia, myocardial ischemia; gastrointestinaldisorders, specifically, mesenteric ischemia; hepatobiliary disorders,specifically, increased bilirubin levels; renal/urinary disorders,specifically, acute renal insufficiency; vascular disorders,specifically, distal limb ischemia; metabolic disorders, specifically,hyponatremia; and skin disorders, specifically, and ischemic lesions.

These reactions are reported voluntarily from a population of uncertainsize. Thus, reliable estimation of frequency or establishment of acausal relationship to drug exposure is unlikely.

Vasopressin has been observed to interact with other drugs. For example,use of vasopressin with catecholamines is expected to result in anadditive effect on mean arterial blood pressure and other hemodynamicparameters. Use of vasopressin with indomethacin can prolong the effectof vasopressin on cardiac index and systemic vascular resistance.Indomethacin more than doubles the time to offset for vasopressin'seffect on peripheral vascular resistance and cardiac output in healthysubjects.

Further, use of vasopressin with ganglionic blocking agents can increasethe effect of vasopressin on mean arterial blood pressure. Theganglionic blocking agent tetra-ethylammonium increases the pressoreffect of vasopressin by 20% in healthy subjects.

Use of vasopressin with furosemide increases the effect of vasopressinon osmolar clearance and urine flow. Furosemide increases osmolarclearance 4-fold and urine flow 9-fold when co-administered withexogenous vasopressin in healthy subjects.

Use of vasopressin with drugs suspected of causing SIADH (Syndrome ofinappropriate antidiuretic hormone secretion), for example, SSRIs,tricyclic antidepressants, haloperidol, chlorpropamide, enalapril,methyldopa, pentamidine, vincristine, cyclophosphamide, ifosfamide, andfelbamate can increase the pressor effect in addition to theantidiuretic effect of vasopressin. Additionally, use of vasopressinwith drugs suspected of causing diabetes insipidus for example,demeclocycline, lithium, foscarnet, and clozapine can decrease thepressor effect in addition to the antidiuretic effect of vasopressin.

Indomethacin can more than double the time to offset for vasopressin'seffect on peripheral vascular resistance and cardiac output in healthysubjects.

Halothane, morphine, fentanyl, alfentanyl and sufentanyl do not impactexposure to endogenous vasopressin.

Use of Vasopressin in Specific Populations.

Vasopressin is a Category C drug for pregnancy.

Due to a spillover into the blood of placental vasopressinase, theclearance of exogenous and endogenous vasopressin increases graduallyover the course of a pregnancy. During the first trimester of pregnancythe clearance is only slightly increased. However, by the thirdtrimester the clearance of vasopressin is increased about 4-fold and atterm up to 5-fold. Due to the increased clearance of vasopressin in thesecond and third trimester, the dose of vasopressin can be up-titratedto doses exceeding 0.1 units/minute in post-cardiotomy shock and 0.07units/minute in septic shock. Vasopressin can produce tonic uterinecontractions that could threaten the continuation of pregnancy. Afterdelivery, the clearance of vasopressin returns to preconception levels.

Overdosage.

Overdosage with vasopressin can be expected to manifest as a consequenceof vasoconstriction of various vascular beds, for example, theperipheral, mesenteric, and coronary vascular beds, and as hyponatremia.In addition, overdosage of vasopressin can lead less commonly toventricular tachyarrhythmias, including Torsade de Pointes,rhabdomyolysis, and non-specific gastrointestinal symptoms. Directeffects of vasopressin overdose can resolve within minutes of withdrawalof treatment.

Pharmacology of Vasopressin.

Vasopressin is a polypeptide hormone that causes contraction of vascularand other smooth muscles and antidiuresis, which can be formulated as asterile, aqueous solution of synthetic arginine vasopressin forintravenous administration. The 1 mL solution contains vasopressin (20units/mL), chlorobutanol, NF 0.5% as a preservative, water forinjection, USP, and sodium acetate buffer adjusted to a pH of 3.8.

The chemical name of vasopressin is Cyclo (1-6)L-Cysteinyl-L-Tyrosyl-L-Phenylalanyl-L-Glutaminyl-L-Asparaginyl-L-Cysteinyl-L-Prolyl-L-Arginyl-L-Glycinamide.Vasopressin is a white to off-white amorphous powder, freely soluble inwater. The structural formula of vasopressin is:

Molecular Formula: C₄₆H₆₅N₁₅O₁₂S₂; Molecular Weight: 1084.23

One mg of vasopressin is equivalent to 530 units. Alternatively, one mgof vasopressin is equivalent to 470 units.

The vasoconstrictive effects of vasopressin are mediated by vascular V₁receptors. Vascular V₁ receptors are directly coupled to phospholipaseC, resulting in release of calcium, leading to vasoconstriction. Inaddition, vasopressin stimulates antidiuresis via stimulation of V₂receptors, which are coupled to adenyl cyclase.

At therapeutic doses, exogenous vasopressin elicits a vasoconstrictiveeffect in most vascular beds including the splanchnic, renal, andcutaneous circulation. In addition, vasopressin at pressor dosestriggers contractions of smooth muscles in the gastrointestinal tractmediated by muscular V₁-receptors and release of prolactin and ACTH viaV₃ receptors. At lower concentrations typical for the antidiuretichormone, vasopressin inhibits water diuresis via renal V₂ receptors. Inpatients with vasodilatory shock, vasopressin in therapeutic dosesincreases systemic vascular resistance and mean arterial blood pressure,and reduces the dose requirements for norepinephrine.

Vasopressin tends to decrease heart rate and cardiac output. The pressoreffect is proportional to the infusion rate of exogenous vasopressin.Onset of the pressor effect of vasopressin is rapid, and the peak effectoccurs within 15 minutes. After stopping the infusion, the pressoreffect fades within 20 minutes. There is no evidence for tachyphylaxisor tolerance to the pressor effect of vasopressin in patients.

At infusion rates used in vasodilatory shock (0.01-0.1 units/minute),the clearance of vasopressin is 9 to 25 mL/min/kg in patients withvasodilatory shock. The apparent half-life of vasopressin at theselevels is <10 minutes. Vasopressin is predominantly metabolized and onlyabout 6% of the dose is excreted unchanged in urine. Animal experimentssuggest that the metabolism of vasopressin is primarily by liver andkidney. Serine protease, carboxipeptidase and disulfide oxido-reductasecleave vasopressin at sites relevant for the pharmacological activity ofthe hormone. Thus, the generated metabolites are not expected to retainimportant pharmacological activity.

Carcinogenesis, Mutagenesis, Impairment of Fertility.

Vasopressin was found to be negative in the in vitro bacterialmutagenicity (Ames) test and the in vitro Chinese hamster ovary (CHO)cell chromosome aberration test. In mice, vasopressin can have an effecton function and fertilizing ability of spermatozoa.

Clinical studies.

Increases in systolic and mean blood pressure following administrationof vasopressin were observed in seven studies in septic shock and eightstudies in post-cardiotomy vasodilatory shock.

EMBODIMENTS

The following non-limiting embodiments provide illustrative examples ofthe invention, but do not limit the scope of the invention.

In some embodiments, the invention provides a pharmaceutical compositioncomprising, in a unit dosage form: a) from about 0.01 mg/mL to about0.07 mg/mL of vasopressin, or a pharmaceutically-acceptable saltthereof; and b) a polymeric pharmaceutically-acceptable excipient in anamount that is from about 1% to about 10% by mass of the unit dosageform or the pharmaceutically-acceptable salt thereof, wherein the unitdosage form exhibits from about 5% to about 10% less degradation of thevasopressin or the pharmaceutically-acceptable salt thereof afterstorage for about 1 week at about 60° C. than does a corresponding unitdosage form, wherein the corresponding unit dosage form consistsessentially of: A) vasopressin, or a pharmaceutically-acceptable saltthereof; and B) a buffer having acidic pH. In some embodiments, thepolymeric pharmaceutically-acceptable excipient comprises a polyalkyleneoxide moiety. In some embodiments, the polymericpharmaceutically-acceptable excipient is a polyethylene oxide. In someembodiments, the polymeric pharmaceutically-acceptable excipient is apoloxamer. In some embodiments, the unit dosage form has an amount ofthe polymeric pharmaceutically-acceptable excipient that is about 1% theamount of the vasopressin or the pharmaceutically-acceptable saltthereof. In some embodiments, the first unit dosage form exhibits about10% less degradation of the vasopressin or thepharmaceutically-acceptable salt thereof after storage for about 1 weekat about 60° C. than does the corresponding unit dosage form. In someembodiments, the unit dosage form further comprises SEQ ID NO. 2. Insome embodiments, the composition further comprises SEQ ID NO. 3. Insome embodiments, the composition further comprises SEQ ID NO. 4. Insome embodiments, the unit dosage form is an injectable of about 1 mLvolume. In some embodiments, the unit dosage form consists essentiallyof: a) about 0.04 mg/mL of vasopressin, or thepharmaceutically-acceptable salt thereof; b) the polymericpharmaceutically-acceptable excipient in an amount that is from about 1%to about 10% by mass of the vasopressin or thepharmaceutically-acceptable salt thereof; and c) a plurality ofpeptides, wherein each of the peptides has from 88% to 90% sequencehomology to the vasopressin or the pharmaceutically-acceptable saltthereof. In some embodiments, one of the plurality of peptides is SEQ IDNO.: 2. In some embodiments, one of the plurality of peptides is SEQ IDNO.:3. In some embodiments, wherein one of the plurality of peptides isSEQ ID NO.: 4. In some embodiments, the buffer has a pH of about 3.5.

What is claimed is:
 1. A pharmaceutical composition comprising, in aunit dosage form: a) from about 0.01 mg/mL to about 0.07 mg/mL ofvasopressin, or a pharmaceutically-acceptable salt thereof; and b) apolymeric pharmaceutically-acceptable excipient in an amount that isfrom about 1% to about 10% by mass of the unit dosage form or thepharmaceutically-acceptable salt thereof, wherein the unit dosage formexhibits from about 5% to about 10% less degradation of the vasopressinor the pharmaceutically-acceptable salt thereof after storage for about1 week at about 60° C. than does a corresponding unit dosage form,wherein the corresponding unit dosage form consists essentially of: A)vasopressin, or a pharmaceutically-acceptable salt thereof; and B) abuffer having acidic pH.
 2. The pharmaceutical composition of claim 1,wherein the polymeric pharmaceutically-acceptable excipient comprises apolyalkylene oxide moiety.
 3. The pharmaceutical composition of claim 1,wherein the polymeric pharmaceutically-acceptable excipient is apolyethylene oxide.
 4. The pharmaceutical composition of claim 1,wherein the polymeric pharmaceutically-acceptable excipient is apoloxamer.
 5. The pharmaceutical composition of claim 1, wherein theunit dosage form has an amount of the polymericpharmaceutically-acceptable excipient that is about 1% the amount of thevasopressin or the pharmaceutically-acceptable salt thereof.
 6. Thepharmaceutical composition of claim 5, wherein the first unit dosageform exhibits about 10% less degradation of the vasopressin or thepharmaceutically-acceptable salt thereof after storage for about 1 weekat about 60° C. than does the corresponding unit dosage form.
 7. Thepharmaceutical composition of claim 1, wherein the unit dosage formfurther comprises SEQ ID NO.
 2. 8. The pharmaceutical composition ofclaim 7, wherein the composition further comprises SEQ ID NO.
 3. 9. Thepharmaceutical composition of claim 8, wherein the composition furthercomprises SEQ ID NO.
 4. 10. The pharmaceutical composition of claim 1,wherein the unit dosage form is an injectable of about 1 mL volume. 11.The pharmaceutical composition of claim 1, wherein the unit dosage formconsists essentially of: a) about 0.04 mg/mL of vasopressin, or thepharmaceutically-acceptable salt thereof; b) the polymericpharmaceutically-acceptable excipient in an amount that is from about 1%to about 10% by mass of the unit dosage form or thepharmaceutically-acceptable salt thereof; and c) a plurality ofpeptides, wherein each of the peptides has from 88% to 90% sequencehomology to the vasopressin or the pharmaceutically-acceptable saltthereof.
 12. The pharmaceutical composition of claim 11, wherein one ofthe plurality of peptides is SEQ ID NO.:
 2. 13. The pharmaceuticalcomposition of claim 12, wherein one of the plurality of peptides is SEQID NO.:3.
 14. The pharmaceutical composition of claim 13, wherein one ofthe plurality of peptides is SEQ ID NO.:
 4. 15. The pharmaceuticalcomposition of claim 1, wherein the buffer has a pH of about 3.5.